22 28695868 AG A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_007194.4(CHEK2):c.1100del(p.Thr367MetfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 152,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHEK2 NM_007194.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:71 U:1 O:2
• Conservation: PhyloP100: 8.67

Genes affected

CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 22-28695868-AG-A is Pathogenic according to our data. Variant chr22-28695868-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 128042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695868-AG-A is described in Lovd as [Pathogenic]. Variant chr22-28695868-AG-A is described in Lovd as [Likely_pathogenic]. Variant chr22-28695868-AG-A is described in Lovd as [Likely_benign]. Variant chr22-28695868-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.1100del	p.Thr367MetfsTer15	frameshift_variant	11/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.1100del	p.Thr367MetfsTer15	frameshift_variant	11/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00204 AC: 509 AN: 248982 Hom.: 0 AF XY: 0.00203 AC XY: 274 AN XY: 135164

Gnomad AFR exome AF: 0.000395

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00873

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00165

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00220 AC: 3205 AN: 1459022 Hom.: 5 Cov.: 30 AF XY: 0.00213 AC XY: 1548 AN XY: 726030

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00848

Gnomad4 NFE exome AF: 0.00236

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74480

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00904

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000595 Hom.: 1

Bravo AF: 0.00100

EpiCase AF: 0.00185

EpiControl AF: 0.00130

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:71Uncertain:1Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

not provided Pathogenic:18Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CHEK2: PVS1, PP1:Strong, PS4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 04, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2020	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of kinase activity (Lee 2001, Wu 2001); Case control studies suggest this variant is associated with several types of cancer, including breast, colon, prostate, gastric, renal, and thyroid (Seppala 2003, The CHEK2 Breast Cancer Consortium 2004, Cybulski 2006, Desrichard 2011, Teodorczyk 2013, Hale 2014, Ma 2014, Siolek 2015, Naslund-Koch 2016, Schmidt 2016, Couch 2017, Decker 2017, Katona 2017, Carlo 2018); This variant is associated with the following publications: (PMID: 11967536, 14648718, 18759107, 27269948, 14612911, 15122511, 17085682, 22114986, 23296741, 25431674, 23946381, 25583358, 26884562, 28418444, 28779002, 28734145, 29978187, 11719428, 11053450, 31948886, 32832836, 31980526, 32854451, 31263571, 32081490, 31447099, 32255556, 15818573, 32285038, 30777372, 31871297, 30957677, 31206626, 28514723, 31263054, 30877237, 31360903, 30612635, 30303537, 30676620, 30113427, 31159747, 30833417, 31090900, 30309722, 30322717, 29767408, 30623166, 29520813, 29445900, 30947698, 30426508, 29506128, 15095295, 30333958, 28135145, 29909963, 28727877, 25186627, 26556299, 28503720, 28802053, 27806230, 27798748, 28195393, 29489754, 28125075, 19768534, 29351919, 28944238, 29146883, 26332814, 29909568, 28874143, 25980754, 26681312, 22527104, 27083775, 26822237, 27153395, 26084796, 26641009, 27716369, 27488870, 21956126, 27751358, 28008555, 27433846, 27443514, 17661168, 16452051, 15087378, 21807500, 12690581, 14648719, 10617473, 15239132, 22006311, 23409019, 22058428, 23109706, 21876083, 22058216, 20722467, 23415889, 22811390, 19030985, 22520019, 21244692, 22691310, 22994785, 15492928, 23329222, 25835597, 24723567) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 04, 2022	PP5, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 11, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2023	The CHEK2 c.1100delC; p.Thr367MetfsTer15 variant (rs555607708) is a well-studied variant that was originally associated with Li-Fraumeni syndrome (Bell 1999) and has since been reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 128042). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, in vitro functional analyses demonstrate a loss of CHEK2 kinase activity, supportive of a pathogenic effect (Lee 2001). This variant is also described as a founder variant in Northern European populations (Cybulski 2004), and is found in the Finnish European population with an allele frequency of 0.87% (219/25124 alleles) in the Genome Aggregation Database. This reduced penetrance variant is associated with an increased breast cancer risk (Bak 2014, Cybulski 2004, Cybulski 2007), and the overall lifetime breast cancer risk for CHEK2 pathogenic variants in general is 20-30% (Slavin 2015). This variant has also been associated with an increased risk of prostate cancer (Naslund-Koch 2016, Pritchard 2016, Wu 2018). There may be additional cancer risks associated with this variant but evidence is incomplete at this time. Based on available information, the c.1100delC variant is considered to be pathogenic. REFERENCES Bak A et al. A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. Hered Cancer Clin Pract. 2014 12(1): 10. Bell DW et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999 286(5449):2528-31. Cybulski C et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004 75(6):1131-5. Cybulski C et al. A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat. 2007 102(1):119-22. Lee SB et al. Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res. 2001 61(22):8062-7. Naslund-Koch C et al. Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study. J Clin Oncol. 2016 Apr 10;34(11):1208-16. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Slavin TP et al. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. Front Oncol. 2015 5:208. Wu Y et al. A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate. 2018 Jun;78(8):607-615. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported most recently on 12-09-2019 by Lab or GTR ID 505849. The variant was also interpretted as pathogenic ad reported on 03-04-2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 21, 2020	The CHEK2 c.1100del (p.Thr367Metfs*15) variant (also known as c.1100delC) alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer and other cancers (PMIDs: 31993860 (2020), 29522266 (2018), 28874143 (2017), 28779002 (2017), 26884562 (2016), 27223485 (2016), 15122511 (2004), 15087378 (2004), 11719428 (2001)). Based on the available information, this variant is classified as pathogenic. -

Familial cancer of breast Pathogenic:14

Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Oct 29, 2022	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 14, 2023	Criteria applied: PVS1,PS3,PS4,PM1 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS3, PS4_STR, BS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 20, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 17, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 10617473, 23329222, 23415889, 22058428, 26332814, 24723567, 29146883] -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 13, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Thr367Metfs*15) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is present in population databases (rs555607708, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This particular variant has been well described in the literature. In a large meta-analysis comprising 16 studies including 26,488 affected individuals and 27,402 controls, women heterozygous for this variant have a relative risk for familial breast cancer of 4.8 (95% CI, 3.3-7.2). The cumulative risk at age 70 years is 37% (95% CI, 26%-56%), compared to 7.8% for the average Caucasian woman in the general population (PMID: 18172190). Although one study has reported that the c.1100del variant confers an approximate 10-fold increased risk of male breast cancer (PMID: 11967536), the results have yet to be confirmed in further studies (PMID: 14648717, 14648718, 14648719, 15488637). ClinVar contains an entry for this variant (Variation ID: 128042). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 24, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 01, 2021	PVS1, PS4, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 2022	The c.1100delC pathogenic mutation, located in coding exon 10 of the CHEK2 gene, results from a deletion of one nucleotide at position 1100, causing a translational frameshift with a predicted alternate stop codon (p.T367Mfs*15). This alteration is located within the kinase domain, and is reported to abolish the kinase activity of CHK2 (Wu X et al. J. Biol. Chem. 2001 Jan;276(4):2971-4). Clinic-based studies have estimated an approximately 2-fold increase in female breast cancer, colorectal cancer, and melanoma risk associated with this alteration (The CHEK2 Breast Cancer Case-Control Consortium. Am. J. Hum. Genet. 2004 Jun;74(6):1175-82; Xiang HP et al. Eur. J. Cancer. 2011 Nov;47(17):2546-51; Weischer M et al. J. Invest. Dermatol. 2012 Feb;132(2):299-303). However, another population-based study found a 2-fold increase in female breast cancer risk and 6-fold increase in stomach cancer risk associated with this alteration, but did not find a statistically significant association with colon cancer or melanoma (Näslund-Koch C et al. J. Clin. Oncol. 2016 Apr;34(11):1208-16). Another study found that risk for estrogen receptor (ER) positive breast cancer was more pronounced than risk for ER-negative breast cancer and estimated that the cumulative risks for development of ER-positive and ER-negative tumors by age 80 in carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom (Schmidt MK et al. J. Clin. Oncol. 2016 Aug;34(23):2750-60). This alteration has also been reported in male breast cancer cohorts (Leedom TP et al. Cancer Genet. 2016 Sep;209:403-407; Hallamies S et al. BMC Cancer 2017 Sep;17:620), and was identified in 5/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2023	This variant deletes 1 nucleotide in exon 11 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A large meta-analysis of breast cancer case-control studies has determined that female carriers of this variant show a relative risk for familial breast cancer of 4.8 (95% CI: [3.3, 7.2]) and cumulative risk at age 70 years of 37% (95% CI: [26, 56]) vs. 7.8% for the population controls (PMID: 18172190). Another meta-analysis has also shown a significant breast cancer risk in heterozygous carriers of this variant (OR=2.75, 95% CI: [2.25, 3.36]) (PMID: 22994785). The ORs and CIs were 2.33 (95% CI: [1.79, 3.05]), 3.72 (95% CI: [2.61, 5.31]) and 2.78 (95% CI: [2.28, 3.39]), respectively, in unselected, family, early-onset breast cancer subgroups in this study. This variant has been observed in individuals affected with colorectal cancer, but whether this variant is associated with increased risk of colorectal cancer remains uncertain (PMID: 21807500, 28135145, 28734145). This variant is well documented as a breast cancer-associated variant in the literature and in the public database (ClinVar variation ID: 128042). This variant has been identified in 591/280390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 14, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 14, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Oct 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variation is a deletion of 1 nucleotide from exon 11 of the CHEK2 mRNA (c.1100delC), causing a frameshift at codon 367. This creates a premature translational stop signal 15 amino acid residues later (p.Thr367Metfs*15) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic. This variant has been well described in the literature (PMID: 18172190). The mutation database ClinVar contains an entry for this variant (Variation ID: 128042). -
Pathogenic, criteria provided, single submitter	research	Hauer Lab, Department Of Pediatric Oncology, Technical University Munich	-	ACMG/AMP, PVS1, PM2, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2021	- -
Pathogenic, criteria provided, single submitter	case-control	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Apr 08, 2022	Data included in classification: Deletion resulting in frameshift (PVS1_vstr) The CHEK2 Breast Cancer Consortium (https://doi.org/10.1038/ng879). 1.1% in healthy individuals/5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003) (PS4_str) Data not included in classification: Weischer et al 2008 (https://doi.org/10.1200/jco.2007.12.5922) OR 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer, OR is above 2 with lower CI ≥1.5. Wu et al., 2001 (PMID: 11053450), assay reports loss of kinase activity in functional studies. -

Colorectal cancer Pathogenic:3

Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Jul 01, 2022	ACMG criteria used to clasify this variant: PVS1, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 09, 2023	Criteria applied: PVS1,PS3,PS4,PM2_SUP -

CHEK2-Related Cancer Susceptibility Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 10, 2015	The c.1100delC (p.Thr367fs) variant in CHEK2 has been associated with increased risk for several types of cancer, including breast, colorectal, and prostate. Me ta-analyses have reported an odds ratio of 2-4 for developing breast, colorectal , or prostate cancer, and a possibly smaller increased risk of malignant melanom a (Weischer 2008, Xiang 2011, Weischer 2012, Yang 2012, Wang 2015). In addition, animal models in mice have shown that this variant causes increased tumor forma tion in multiple cancer sites (Bahassi 2009). This variant has also been reporte d by other clinical laboratories in ClinVar (Variation ID 128042). Of note, this variant has been identified in 0.3% (319/125272) of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 35705950). Therefore, this variant is not expected to cause highly penetrant Men delian disease. In summary, the c.1100delC (p.Thr367fs) variant is an establishe d risk factor for breast, colorectal, and prostate cancers. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 9/2/2020 by Invitae, 2/22/2016 by Ambry Genetics, 12/16/2016 by Myriad, 3/4/2017 by GeneDx, and 9/11/17 by Myriad Women's Health. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CHEK2 c.1100delC (p.Thr367MetfsTer15) variant is a common variant in individuals of European origin and has been investigated in multiple studies in various cancer types. A meta-analysis of ten case-control studies, including 10,860 breast cancer cases and 9,065 controls by the CHEK2 Breast Cancer Case-Control Consortium (2004) found a statistically significant association between carrying the p.Thr367MetfsTer15 variant and increase in risk of breast cancer (OR=2.34). The association of the p.Thr367MetfsTer15 variant and increased risk of breast cancer was also supported by Bernstein et al. (2006) (OR=6.65) and Weischer et al. (2007) (OR=3.2). Weischer et al. (2007) also found an association between the variant and increased risk of prostate cancer (OR=2.3) and colorectal cancer (OR=1.6). Weischer et al. (2012) found an association of the p.Thr367MetfsTer15 variant and increased risk of malignant melanoma in both a case-control study (OR=1.79) and a meta-analysis (OR=1.81). The p.Thr367MetfsTer15 variant has also been identified in patients with Li-Fraumeni syndrome (Bell et al. 1999), colon, kidney, prostate, and thyroid cancers (Cybulski et al. 2004), ovarian cancer (Walsh et al. 2011), and uterine cancer (Pennington et al. 2013), though the associated risks for these cancers due to this variant are unclear at this time. Studies by Lee et al. (2001) found a lack of kinase activity and evidence of loss of heterozygosity in a tumor sample from a patient carrying the germline p.Thr367MetfsTer15 variant. The highest allele frequency reported in the 1000 Genomes database is 0.0202 in the Finnish population. Although an association with the p.Thr367MetfsTer15 variant and susceptibility to different cancers is widely reported, the increase in risk is low to moderate. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Li-Fraumeni syndrome 2 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 16, 2024	Criteria applied: PVS1,PS3,PS4 -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Jun 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 07, 2021	- -

Breast and colorectal cancer, susceptibility to Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant is also referred to as c.1100delC (p.Thr367MetfsTer15) (NM_007194.3) in the literature. This deletion in exon 12 of 16 causes a frameshift and a premature stop codon at residue 424 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). The c.1229del (p.Thr410MetfsTer15) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.2% (585/275092) and is present in the homozygous state at a frequency of 0.0004% (1/275092). This variant is enriched in the European (Finnish) population (MAF=0.87%). Based on two large case-control studies, the relative risk for female breast cancer associated with the c.1229del variant was 3.0 (90% CI, 2.6-3.5) (PMID: 26014596, 15122511, 23109706). Additionally, a meta-analysis reported a relative risk of 1.88 (95% C.I. 1.29-2.73) for colorectal cancer associated with the c.1229del variant (PMID: 23946381). The c.1229del variant has also been associated with an increased risk of prostate cancer (PMID: 26629066) and other cancers (PMID: 26884562, 21956126). Based on the available evidence, the c.1229del (p.Thr410MetfsTer15) variant is classified as Pathogenic. -

Carcinoma of pancreas Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

CZECANCA consortium

Mar 04, 2021

- -

Leiomyosarcoma;C1458155:Breast neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genome Sciences Centre, British Columbia Cancer Agency

-

Positive family history of early breast cancer (niece diagnosed at age 35). Whole genome sequencing (blood and tumor) and whole transcriptome sequencing (tumor) also revealed the germline CHEK2:c.1100delC pathogenic variant, which is considered a moderate penetrance allele for breast cancer. -

Breast neoplasm Pathogenic:1

Pathogenic, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

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CHEK2-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2024

The CHEK2 c.1100delC variant is predicted to result in a frameshift and premature protein termination (p.Thr367Metfs*15). This variant has been reported to be causative for hereditary breast cancer and uterine serous carcinoma (Bell et al. 1999. PubMed ID: 10617473; Pennington et al. 2013. PubMed ID: 22811390). In a large Danish study, this variant was associated with a statistically-significant increased risk of breast cancer (hazard ratio [HR]: 2.08, 95% CI: 1.51-2.85) and stomach cancer (HR: 5.76, 95%CI: 2.12-15.6; Näslund-Koch et al. 2016. PubMed ID: 26884562). In another study consisting of more than 80,000 breast cancer patients and age-appropriate controls, this variant was reported to have a higher risk for estrogen receptor-positive breast cancer (Schmidt et al. 2016. PubMed ID: 27269948). In addition, this variant has been associated with prostate (Hale et al. 2014. PubMed ID: 25431674) and colorectal cancers (Wasielewski et al. 2008. PubMed ID: 18676774; Xiang et al. 2011. PubMed ID: 21807500). Functional studies have shown that the c.1100del variant impairs CHEK2 activity (Lee et al. 2001. PubMed ID: 11719428; Roeb et al. 2012. PubMed ID: 22419737). This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128042/). Loss-of-function variants in CHEK2 are known to be pathogenic. This variant is interpreted as pathogenic. -

TUMOR PREDISPOSITION SYNDROME 4, BREAST/PROSTATE/COLORECTAL Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2006

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Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

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Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 19, 2021

Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive -

Li-Fraumeni syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 26, 2023

Criteria applied: PVS1,PS3,PS4 -

Breast cancer, susceptibility to Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 22, 2021

DNA sequence analysis of the CHEK2 gene demonstrated a single base pair deletion in exon 11, c.1100del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 15 amino acids downstream of the sequence change, p.Thr367Metfs*15. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CHEK2 protein with potentially abnormal function. In vitro functional studies have demonstrated that CHEK2 c.1100del change results in loss of kinase activity and the inability to phosphorylate Cdc25C, supportive of a pathogenic effect (PMIDs: 11719428, 11053450). This pathogenic sequence change is a well-known founder pathogenic variant with relative frequency in European populations. It is associated with an increased risk for cancer and has been described in multiple patients with CHEK2-related cancers, including breast cancer, lung cancer, thyroid cancer, gastric cancer, renal cancer, lymphoma and in individuals with possible Li-Fraumeni syndrome (PMID: 21956126, 23296741, 26884562, PMID: 26506619). -

Colitis;C0018932:Hematochezia;C0040034:Thrombocytopenia;C0578878:Inflammation of the large intestine Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

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Malignant tumor of prostate Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Mar 15, 2024

Criteria applied: PVS1,PS3,PS4_MOD -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CHEK2 p.Thr367Metfs*15 variant was identified in 1290 of 102960 proband chromosomes (frequency: 0.013) from individuals or families with breast, prostate, and colorectal cancer and was present in 1222 of 292928 control chromosomes (frequency: 0.004) from healthy individuals (Adank 2011, Cybulski 2004, Cybulski 2006, Dong 2003, Easton 2004, Ruijs 2009, Silva 2014, Weischer 2008, Xiang 2011, Yang 2012). The variant was also identified in the following databases: dbSNP (ID: rs555607708) as "With Pathogenic allele", ClinVar (12x, pathogenic), Clinvitae (6x, pathogenic), Cosmic (1x, salivary gland tumour sample), and the Zhejiang Colon Cancer Database (48x). The variant was not identified in the MutDB database. The variant was identified in control databases in 585 of 275092 chromosomes at a frequency of 0.002 (Genome Aggregation Consortium Feb 27, 2017). Of note, it was identified in the Finnish population in 221 of 25794 chromosomes (freq. 0.009) and in the European population in 319 of 125272 chromosomes (freq. 0.003). The c.1100delC variant is an established breast cancer susceptibility allele and is associated with a two- to three-fold increased risk for breast cancer at a median age of 53 years (Naslund-Koch 2016). This variant is also associated with an increased risk of additional cancer types, including prostate, colon, and others (Cybulski 2004, Xiang 2011). Functional studies involving wild-type and mutant CHEK2 proteins expressed in insect cells showed that the p.Thr367Metfs*15 protein lacks kinase activity, supportive of a pathogenic effect (Wu 2001). The c.1100delC variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 367 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Predisposition to cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

May 24, 2022

The CHEK2 c.1100del (p.Thr367MetfsTer15) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has been widely reported to be associated with cancer susceptibility, including significant associations with increased risk of breast cancer in large meta-analysis studies (odds ratios ~2-5, PMID: 18172190, 22994785). This variant has also been reported in individuals with colon, prostate, gastric, kidney, and thyroid cancer (PMID: 14612911, 15087378, 15492928, 16880452, 21807500, 23296741, 25431674, 25583358, 26884562). This change has an overall frequency of 0.21% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) and has been described as a founder variant in Northern European populations (PMID: 15087378). In summary, this variant meets criteria to be classified as pathogenic with evidence indicating lower penetrance. -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate Pathogenic:1

Pathogenic, criteria provided, single submitter

research

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Sep 26, 2022

PVS1, PS4, PS3_Supporting -

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 25, 2019

Variant summary: CHEK2 c.1100delC (p.Thr367MetfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.002 in 248982 control chromosomes (gnomAD). Although this variant was found at a relatively high frequency in controls, this is a well-known founder mutation that is known to be relatively frequent in European populations. c.1100delC has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and also as risk factor for several cancer types (breast, ovarian, prostate, colon, etc.). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this variant leads to loss of damage response and kinase activity (Lee_2001, Roeb_2012). Eighteen other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Bone osteosarcoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Jul 26, 2021

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Familial cancer of breast;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C1836482:Li-Fraumeni syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

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Neoplasm of ovary Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Jul 28, 2023

The variant CHEK2:c.1100delC, p.(Thr367fs), which is located in the coding exon 11 of the CHEK2 gene, results from a deletion of a nucleotide at position 1100. The variant causes a frameshift that results on the replace of threonine residue at protein position 367 by methionine and a premature stop codon follows after further 15 amino acids. The premature stop codon is predicted to cause protein truncation/absent and nonsense mediated decay in a gene where loss-of-function is a mechanism of disease. Multiple studies has shown that the variant is statistically significant associated to increased risk of breast and other type of cancer, including ovarian cancer (PMID: 16492927; 23109706; 21956126; 16880452; 28727877; 37055167). In one study, tumours were also detected statistically significantly more frequently in mice with the CHEK2 c.1100delC variant as compared to wild-type controls (PMID: 19805189). This variant is a known founder variant in the overall population and occurs with an allele frequency of < 1 % in gnomAD. The variant is classified as Pathogenic. -

Astrocytoma Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratory of Molecular Neuropathology, The University of Texas Health Science Center at Houston

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs555607708; hg19: chr22-29091856; COSMIC: COSV60419771; COSMIC: COSV60419771;