ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.409C>T (p.Arg137Ter) (rs730881701)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254656 SCV000211017 pathogenic not provided 2018-10-23 criteria provided, single submitter clinical testing This pathogenic variant is denoted CHEK2 c.409C>T at the cDNA level and p.Arg137Ter (R137X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in at least two individuals with breast cancer as well as in three individuals who underwent multi-gene panel testing for hereditary cancer (Leedom 2016, Sun 2017). We consider CHEK2 Arg137Ter to be pathogenic.
Ambry Genetics RCV000160452 SCV000274055 pathogenic Hereditary cancer-predisposing syndrome 2020-09-16 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 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 2020-10-02 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. This variant is present in population databases (rs730881701, ExAC 0.004%). This variant has been observed in individuals affected with breast cancer (PMID: 28724667), and who underwent genetic testing for the risk of hereditary cancer, including breast cancer (PMID: 27751358). ClinVar contains an entry for this variant (Variation ID: 182452). Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). 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; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000160452 SCV000903769 pathogenic Hereditary cancer-predisposing syndrome 2021-01-12 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). 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 ( 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 Karolinska University Hospital,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 and 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.
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.

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