rs536907995

chr22-28734664-G-Achr22-28734664-G-C

Variant summary

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

The NM_007194.4(CHEK2):c.58C>T(p.Gln20Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: CHEK2 NM_007194.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 2.29

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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 361 pathogenic variants in the truncated region.
• PP5: Variant 22-28734664-G-A is Pathogenic according to our data. Variant chr22-28734664-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 133887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734664-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.58C>T	p.Gln20Ter	stop_gained	2/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.58C>T	p.Gln20Ter	stop_gained	2/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152082 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000141 AC: 35 AN: 247462 Hom.: 0 AF XY: 0.000201 AC XY: 27 AN XY: 134030

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1461766 Hom.: 0 Cov.: 33 AF XY: 0.0000935 AC XY: 68 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152200 Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5 AN XY: 74416

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Biotechnology, Institute of Science, Nirma University	Oct 26, 2023	The CHEK2 constitutional genetic variant leads to a premature truncation of the protein at 20 amino acids leading to loss of the domains crucial for the interaction of proteins like ATM/BRCA2 which are master regulator of the DNA damage repair pathways. The outcome of this mutation could be observed in various cancers specially breast and ovarian cancers, which also corroborates with the familial breast cancer history of the proband, although the proband is yet asymptomatic. Hence, keeping in view the functional effect the variant has been classified pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Gln20*) 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 (rs536907995, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 26023681, 27039729, 27510020, 28724667). ClinVar contains an entry for this variant (Variation ID: 133887). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Sep 13, 2023	A pathogenic mutation was detected in the CHEK2 gene (c.58C>T).This sequence change creates a premature translational stop signal (p.Gln20*) in the CHEK2 gene. This variant is expected to result in an absent or non-functional protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant Not observed at a significant frequency in large population cohorts (gnomAD). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 26023681, 27039729, 27510020, 28724667). ClinVar contains an entry for this variant (Variation ID: 133887) classified as pathogenic with no conflict . For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 26, 2022	This nonsense variant is predicted to cause the premature termination of CHEK2 protein synthesis. In addition, it has been reported in individuals with breast and/or ovarian cancer in the published literature (PMIDs: 26023681 (2015), 27510020 (2016), 28724667 (2017), 32658311 (2021), and 32885271 (2021)). Based on the available information, this variant is classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 08, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2022	Nonsense 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 (gnomAD); Observed in individuals with a personal or family history of CHEK2-related cancers in published literature (Foley 2015, Baloch 2016, Scarpa 2017, Sun 2017, Fan 2018, Akcay 2020); This variant is associated with the following publications: (PMID: 26023681, 28724667, 28199314, 27039729, 24728327, 27510020, 29356917, 28779002, 29922827, 28553140, 32658311) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 20, 2023	This variant changes 1 nucleotide in exon 2 of the CHEK2 gene, creating a 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 cancer (PMID: 27039729, 28724667, 32658311, 32885271), an individual affected with ovarian cancer (PMID: 32885271) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000005). This variant has also been observed in an individual affected with breast and ovarian cancer, who carried a pathogenic variant in the BRCA2 gene (PMID: 26023681). This variant is found at a high frequency in the South Asian population (0.1145%, 35/30544 chromosomes) by the Genome Aggregation Database (gnomAD), suggesting its penetrance may be reduced relative to other pathogenic CHEK2 alleles. Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 16, 2021	The p.Q20* pathogenic mutation (also known as c.58C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 58. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This alteration was detected in conjunction with a pathogenic BRCA2 mutation in an individual diagnosed with breast cancer at ages 37 and 61 and ovarian cancer at age 56 (Foley SB et al. EBioMedicine. 2015 Jan;2:74-81). This alteration has also been observed in breast cancer cohorts (Baloch AH et al. Asian Pac. J. Cancer Prev. 2016;17:1089-92; Sun J et al. Clin Cancer Res 2017 Oct;23(20):6113-6119). In one case-control study, this alteration was not identified in 13087 breast cancer cases but was seen in 1/5488 control individuals in the United Kingdom; of note, study subjects were under the age of 55 years (Decker B et al. J Med Genet 2017 11;54(11):732-741). 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. -

Familial ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CHEK2 p.Gln20* variant was identified in 2 of 858 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Baloch 2016, Foley 2014). The variant was also identified in dbSNP (ID: rs536907995) as "With Pathogenic allele", and in ClinVar (classified as likely pathogenic by GeneDx, Color Genomics; as pathogenic by Invitae, Counsyl). The variant was not identified in the Zhejiang University database. The variant was identified in control databases in 36 of 242162 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). It was observed in the South Asian population in 36 of 30708 chromosomes (freq: 0.001); it was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, and Finnish populations. The c.58C>T variant leads to a premature stop codon at position 20 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease in CHEK2-associated cancers and is the type of variant expected to cause the disorder. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Li-Fraumeni syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Apr 04, 2024

- -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Sep 12, 2021

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	35
Dann	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;D
Vest4		0.72
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs536907995; hg19: chr22-29130652;