ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1555C>T (p.Arg519Ter) (rs200432447)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116005 SCV000215386 pathogenic Hereditary cancer-predisposing syndrome 2017-08-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000116005 SCV000689671 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-07 criteria provided, single submitter clinical testing
Counsyl RCV000471222 SCV000786152 likely pathogenic Familial cancer of breast 2018-03-06 criteria provided, single submitter clinical testing
GeneDx RCV000212474 SCV000149914 likely pathogenic not provided 2018-11-12 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1555C>T at the cDNA level and p.Arg519Ter (R519X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA). Due to the position of the variant, nonsense-mediated decay is not expected to occur, but the variant might cause loss of normal protein function through protein truncation as the last 25 amino acids are lost. The disrupted region at the end of the gene includes a portion of the nuclear localization signal (Roeb 2012). CHEK2 Arg519Ter has been reported in individuals with early-onset breast or colorectal cancer undergoing hereditary cancer panel testing as well as at least one individual with prostate cancer (Maxwell 2014, Tung 2015, Yorczyk 2015, Leedom 2016, Gardner 2018, Wu 2018). Based on currently available evidence, we consider this variant to be likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000589100 SCV000698785 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-15 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1555C>T variant results in a premature termination codon 24 residues from the end of the protein, predicted to cause a truncated or absent CHEK2 protein (R519X), which is a commonly known mechanism for cancer due to CHEK 2 mutations. Mutation Taster predicts a damaging outcome for this variant, but functional studies have not been carried out. This variant is not found in 107584 control chromosomes, but has been cited in at least 3 breast cancer patients in the literature. In addition, several clinical laboratories classified this variant as pathogenic. Taken together, this is a disease variant and was classified as pathogenic.
Invitae RCV000471222 SCV000550494 likely pathogenic Familial cancer of breast 2018-11-08 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the CHEK2 mRNA at codon 519 (p.Arg519*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 25 amino acids of the CHEK2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with breast and/or ovarian cancer as well as individuals undergoing genetic testing for breast cancer risk (PMID: 25503501, 29020732, 27751358). ClinVar contains an entry for this variant (Variation ID: 128064). This variant is expected to disrupt a portion of the C-terminal region of the CHEK2 protein containing the nuclear localization signal (NLS) (residues Pro515-Pro522). Although functional studies have not been performed for this particular variant, disruption of the NLS likely impairs CHEK2 function, as variants within the NLS result in CHEK2 mislocalization to the cytoplasm (PMID: 12909615, 18004398, 24879340). This suggests that disruption of this region of the CHEK2 protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
University of Washington Department of Laboratory Medicine,University of Washington RCV000210124 SCV000266167 likely pathogenic Breast and colorectal cancer, susceptibility to 2017-07-11 no assertion criteria provided clinical testing

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