ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1368dup (p.Glu457fs) (rs730881700)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212460 SCV000211014 pathogenic not provided 2018-05-09 criteria provided, single submitter clinical testing This duplication of one nucleotide in CHEK2 is denoted c.1368dupA at the cDNA level and p.Glu457ArgfsX33 (E457RfsX33) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TCTC[dupA]GAGA. The duplication causes a frameshift, which changes a Glutamic Acid to an Arginine at codon 457, and creates a premature stop codon at position 33 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. CHEK2 c.1368dupA has been reported in at least one individual with breast cancer (Tung 2016). We consider this variant to be pathogenic.
Ambry Genetics RCV000160450 SCV000215087 pathogenic Hereditary cancer-predisposing syndrome 2017-09-22 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)
Invitae RCV000473927 SCV000550523 pathogenic Familial cancer of breast 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu457Argfs*33) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs730881700, ExAC 0.02%). This variant has been reported in the literature in individuals affected with breast cancer (PMID: 26681312, 26976419, 28724667). ClinVar contains an entry for this variant (Variation ID: 182450). Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000473927 SCV000677807 likely pathogenic Familial cancer of breast 2017-01-09 criteria provided, single submitter clinical testing
Color RCV000160450 SCV000684584 pathogenic Hereditary cancer-predisposing syndrome 2015-11-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000473927 SCV000917230 pathogenic Familial cancer of breast 2018-02-02 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1368dupA (p.Glu457ArgfsX33) 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. At least one publication reports experimental evidence evaluating an impact on protein function, which demonstrated that the truncated protein product is localizes exclusively to the cytoplasm, suggesting the 1368dupA mutant to be nonfunctional, as the main substrates for CHK2 phosphorylation are located in the nucleus (Staalesen 2004). The variant allele was found at a frequency of 2.4e-05 in 245848 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (2.4e-05 vs 0.00031), allowing no conclusion about variant significance; moreover pseudogene interference might also affect the validity of these frequency results. c.1368dupA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Tung 2016, Susswein 2016, Leedom 2016). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Snyder Lab, Genetics Department,Stanford University RCV000722050 SCV000853094 likely pathogenic CHEK2-Related Cancer Susceptibility 2017-01-01 no assertion criteria provided research

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