ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2979G>A (p.Trp993Ter) (rs80358544)

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Total submissions: 8
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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) RCV000031393 SCV000300579 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000203665 SCV000072110 pathogenic Hereditary breast and ovarian cancer syndrome 2018-05-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 993 (p.Trp993*). It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic. This particular variant has been reported in a family with 3 individuals affected with breast cancer and 1 with ovarian cancer (PMID: 16170354). This paper also demonstrated in lymphoblastoid cell lines established from the carriers that mRNA abundance is ~40% of normal, consistent with nonsense-mediated decay of the mRNA transcript with the premature stop codon. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162915 SCV000213402 pathogenic Hereditary cancer-predisposing syndrome 2014-08-29 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 RCV000031393 SCV000326796 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000162915 SCV000683518 pathogenic Hereditary cancer-predisposing syndrome 2015-03-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000203665 SCV000694657 pathogenic Hereditary breast and ovarian cancer syndrome 2016-12-19 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2979G>A (p.Trp993X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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.3103G>T, p.Glu1035X; c.3187C>T, p.Gln1063X; c.3226_3230delGTAGT, p.Val1076fsX3). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120312 control chromosomes, but has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031393 SCV000053998 pathogenic Breast-ovarian cancer, familial 2 2012-02-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031393 SCV000146155 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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