Submissions for variant NM_007194.4(CHEK2):c.409C>T (p.Arg137Ter)

gnomAD frequency: 0.00001  dbSNP: rs730881701

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254656	SCV000211017	pathogenic	not provided	2022-12-28	criteria provided, single submitter	clinical testing	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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30322717, 32980694, 32805687, 32923877, 29922827, 35281821, 28888541, 27751358, 28724667, 28492532, 28779002, 29356917, 30303537, 29625052, 30287823, 32113160, 32658311, 31589614, 34426522, 33558524, 35418818, 34299313, 35710434)
Ambry Genetics	RCV000160452	SCV000274055	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-28	criteria provided, single submitter	clinical testing	The p.R137* pathogenic mutation (also known as c.409C>T), located in coding exon 2 of the CHEK2 gene, results from a C to T substitution at nucleotide position 409. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been reported in multiple patients undergoing multi-gene panel testing for personal history of breast cancer (Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Akcay IM et al. Int J Cancer, 2021 01;148:285-295; Guglielmi C et al. Int J Mol Sci, 2021 Jul;22:(14); Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). 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.
Invitae	RCV000229303	SCV000289685	pathogenic	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg137*) 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 (rs730881701, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 182452). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763477	SCV000894259	pathogenic	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160452	SCV000903769	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-16	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 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: 28724667, 28779002, 29356917, 29922827, 30287823, 34299313). This variant has been identified in 6/251304 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254656	SCV001134166	pathogenic	not provided	2019-05-17	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Genomic Medicine Lab, University of California San Francisco	RCV001007871	SCV001167572	pathogenic	Congenital heart defects, multiple types, 3	2017-12-21	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000254656	SCV001449538	pathogenic	not provided	2019-10-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526967	SCV001737749	pathogenic	Hereditary breast ovarian cancer syndrome	2021-05-27	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.409C>T (p.Arg137X) 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 2.4e-05 in 251304 control chromosomes (gnomAD). c.409C>T has been reported in the literature in multiple individuals affected with breast cancer and/or ovarian cancer (Leedom_2016, Sun_2017, Moradian_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000254656	SCV002019289	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
DASA	RCV002221501	SCV002499412	pathogenic	CHEK2-Related Cancer Susceptibility	2022-04-10	criteria provided, single submitter	clinical testing	The c.409C>T;p.(Arg137*) variant creates a premature translational stop signal in the CHEK2 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 182452; PMID: 33558524; 29356917) - PS4. The variant is present at low allele frequencies population databases (rs730881701 – gnomAD 0.0001315%; ABraOM 0.000427 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Myriad Genetics, Inc.	RCV000229303	SCV004045635	pathogenic	Familial cancer of breast	2023-06-23	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000229303	SCV004217550	pathogenic	Familial cancer of breast	2023-09-18	criteria provided, single submitter	clinical testing
Center of Medical Genetics and Primary Health Care	RCV000229303	SCV000987253	pathogenic	Familial cancer of breast	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria The CHEK2 variant p.Arg137Ter is in exon 3, in a kinase domain and in a mutation hotspot of 17 pathogenic variants (PM1 Pathogenic Moderate). This nonsense variant truncates the protein and thus makes it non-functional which is an established disease mechanism in disease (PVS1 Pathogenic Very Strong). The allele frequency in GnomAD exomes is 0.0000239 which is less the threshold 0.0001 for recessive gene CHEK2, and this variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). 4 pathogenic predictions from DANN, EIGEN, FATHMM-MKL and MutationTaster versus no benign predictions support its deleterious effect (PP3 Pathogenic Supporting). In our study this variant was found in a 54-year-old female with unilateral breast cancer and a family history. Based on the evidence above we classified this variant as a Pathogenic.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000254656	SCV002035244	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000254656	SCV002037318	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162676	SCV002758248	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research