ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2978G>A (p.Trp993Ter) (rs80358543)

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Total submissions: 5
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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) RCV000113124 SCV000300578 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113124 SCV000326795 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000485157 SCV000569754 pathogenic not provided 2016-03-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2978G>A at the cDNA level and p.Trp993Ter (W993X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Using alternate nomenclature, this variant would be defined as 3206G>A. Although this variant has not, to our knowledge, been reported in the literature, the adjacent variant BRCA2 c.2979G>A, which also results in a premature stop codon at this residue (p.Trp993Ter), has been reported in a family with breast and ovarian cancer (Ware 2006). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000637724 SCV000759197 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp993*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 126001). A different variant (c.2979G>A) giving rise to the same protein effect observed here (p.Trp993*) has been reported in a family with 3 individuals affected with breast cancer and 1 with ovarian cancer (PMID: 16170354). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113124 SCV000146154 pathogenic Breast-ovarian cancer, familial 2 1998-11-30 no assertion criteria provided clinical testing

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