ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6065C>G (p.Ser2022Ter) (rs80358843)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113522 SCV000300975 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000217928 SCV000278494 pathogenic Hereditary cancer-predisposing syndrome 2016-10-12 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)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113522 SCV000327343 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000429027 SCV000512374 pathogenic not provided 2018-09-10 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.6065C>G at the cDNA level and p.Ser2022Ter (S2022X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as BRCA2 6293C>G using alternate nomenclature, has been observed in association with breast cancer (Loman 2000, Staff 2001, Jonsson 2005, Nik-Zainal 2012, Winter 2016, Davies 2017), and is considered pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000503943 SCV000592026 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000503943 SCV000694933 pathogenic Hereditary breast and ovarian cancer syndrome 2019-02-21 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6065C>G (p.Ser2022X) 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 (e.g. c.6079dupA, p.Arg2027fsX22; c.6270_6271delTA; p.His2090fsX9; c.6275_6276delTT, p.Leu2092fsX7). The variant allele was found at a frequency of 4.1e-06 in 245756 control chromosomes (gnomAD). c.6065C>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Loman 2000, Bosdet 2013, Lin 2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113522 SCV000146757 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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