rs587780174

chr22-28695238-TA-T

Variant summary

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

The NM_007194.4(CHEK2):c.1263del(p.Ser422ValfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000591 in 152,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L421L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHEK2 NM_007194.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24 O:2
• Conservation: PhyloP100: -0.387

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 22-28695238-TA-T is Pathogenic according to our data. Variant chr22-28695238-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.1263del	p.Ser422ValfsTer15	frameshift_variant	12/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.1263del	p.Ser422ValfsTer15	frameshift_variant	12/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000440 AC: 11 AN: 250264 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135312

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000247 AC: 346 AN: 1403334 Hom.: 2 Cov.: 24 AF XY: 0.000237 AC XY: 166 AN XY: 701402

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000321

Gnomad4 OTH exome AF: 0.0000855

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74436

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000378

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2023	- -
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. -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS4_STR -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Ser422Valfs*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 (rs587780174, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast, prostate, bladder, colon and urethral cancer (PMID: 21244692, 24113346, 24556621, 26681312). ClinVar contains an entry for this variant (Variation ID: 128053). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:6

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	curation	Sema4, Sema4	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 11, 2023	This variant deletes 1 nucleotide in exon 12 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. This variant has been reported in individuals affected with breast, bladder, colon, hematological, prostate and urethral cancer (PMID: 21244692, 24556621, 26534844, 26681312, 27273131, 33803639). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 25/60466 cases and 5/53461 unaffected controls (OR=4.422 (95%CI 1.693 to 11.552)) (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000325). This variant has been identified in 13/281654 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, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 04, 2021	The c.1263delT pathogenic mutation, located in coding exon 11 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1263, causing a translational frameshift with a predicted alternate stop codon (p.S422Vfs*15). This mutation has been reported in individuals with multiple cancer types including female breast, male breast, prostate, urethral, bladder, renal, pancreatic, colon, and sarcoma (Le Calvez-Kelm F et al. Breast Cancer Res, 2011 Jan;13:R6; Leongamornlert D et al. Br. J. Cancer, 2014 Mar;110:1663-72; Mauer CB et al. Genet. Med., 2014 May;16:407-12; Byers H et al. Eur J Hum Genet, 2016 11;24:1591-1597; Susswein LR et al. Genet Med, 2016 08;18:823-32; Leedom TP et al. Cancer Genet, 2016 09;209:403-407; AlDubayan SH et al. JAMA Oncol, 2019 Apr;5:514-522; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Smith PS et al. Genes Chromosomes Cancer, 2021 01;60:5-16; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In one study, this variant was reported in 25/60,466 breast cancer cases as well as 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 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; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as c.1392delT (p.Ser465ValfsX15); This variant is associated with the following publications: (PMID: 25431674, 24113346, 28779002, 29961768, 29625052, 21244692, 26681312, 24556621, 27273131, 27751358, 26787654, 28152038, 26534844, 29287968, 29520813, 29909963, 24763289, 30676620, 31263054, 31447099, 32832836) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2018	DNA sequence analysis of the CHEK2 gene demonstrated a one base pair deletion in exon 12, c.1263del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon fourteen amino acids downstream of the mutation, p.Ser422Valfs*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. This pathogenic sequence change has previously been described in patients with CHEK2-related cancers (PMIDs: 21244692, 24113346, 24556621, 26681312). -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 10, 2022	This frameshift variant alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 27273131 (2016), 26534844 (2016), 21244692 (2011)) and prostate cancer (PMID: 24556621 (2014)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CHEK2 p.Ser422ValfsX15 variant was identified in 22 of 115016 proband chromosomes (frequency: 0.0002) from individuals or families with breast, prostate, and other types of cancer (Byers 2016, Calvez-Kelm 2011, Leedom 2016, Leongamornlert 2014, Mauer 2014, Susswein 2016). The variant was also identified in the following databases: dbSNP (ID: rs587780174) as "With Pathogenic allele", ClinVar (4x pathogenic), and Clinvitae (3x pathogenic). The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was also not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In a study by Leongamornlert (2014), this variant was found to segregate with 2 of 3 affected family members with prostate cancer. The c.1263delT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 422 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. -

CHEK2-related cancer predisposition Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 01, 2018	The CHEK2 c.1263delT (p.Ser422ValfsTer15) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ser422ValfsTer15 variant has been reported in at least six studies in at least 25 individuals undergoing hereditary cancer testing or diagnosed with various cancer types (La Calvez-Kelm et al. 2011; Leongamornlert et al. 2014; Mauer et al. 2014; Susswein et al. 2015; Byers et al. 2016; Leedom et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00010 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of frameshift variants, the p.Ser422ValfsTer15 variant is classified as likely pathogenic for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 10-21-2019 by Lab Invitae. 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. -

Li-Fraumeni syndrome 2 Pathogenic:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 04-28-2017 by Lab Invitae. 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	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 28, 2023	PVS1, PS4 -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 28, 2022

- -

Predisposition to cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 05, 2022

The CHEK2 c.1263del (p.Ser422ValfsTer15) 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 reported in individuals with breast, colon, prostate, bladder, and urethral cancer (PS4; PMID: 21244692, 24556621, 26534844, 26681312, 27273131, 33803639). This variant has a maximum subpopulation frequency of 0.0086% in gnomAD v2.1.1 (https:// gnomad.broadinstitute.org/). Other truncating variants in exon 12 have been reported in individuals with CHEK2-associated cancers and are known to be pathogenic (PM5_supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM5_supporting. -

Malignant tumor of prostate Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genomics England Pilot Project, Genomics England

-

- -

Familial cancer of breast;C0346629:Colorectal cancer;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

Feb 17, 2022

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 26, 2017

Variant summary: The CHEK2 c.1263delT (p.Ser422Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent CHEK2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is expected to truncate protein kinase domain. Truncations downstream of this position have been classified as pathogenic/likely pathogenic by our laboratory and others (e.g. p.Arg519X, c.1434delA, etc.). This variant was found in 6/117456 control chromosomes at a frequency of 0.0000511, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). This variant has been reported in multiple cancer patients including breast and prostate cancer and is classified as pathogenic in literature and by multiple clinical diagnostic laboratories/reputable databases. Taken together, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780174; hg19: chr22-29091226;