ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.93G>T (p.Trp31Cys) (rs80359214)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565952 SCV000661412 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113126 SCV000146157 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Invitae RCV000045811 SCV000073824 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-12-29 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 31 of the BRCA2 protein (p.Trp31Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (rs80359214, ExAC no frequency). This variant has been reported in families affected with breast and/or ovarian cancer (PMID: 22678057, Invitae). ClinVar contains an entry for this variant (Variation ID: 52830). Experimental studies have shown that this missense change disrupts the binding of BRCA2 to PALB2, thereby abolishing the normal cellular functioning of BRCA2 (PMID: 16793542, 22678057, 24285729, 20215541, 22194698, 19609323). Studies also suggest that this missense change may induce skipping of exon 3, and loss of exon 3 has been reported in several families affected with breast and/or ovarian cancer (PMID: 22678057, 20215541, 9537232, 21939546, 18363094). This missense change is located within the functionally conserved PALB2-binding domain of the BRCA2 protein (PMID: 19609323), and previously reported BRCA2 missense mutations and deletions have been found within this domain (PMID: 16793542, 22678057, 21939546). These observations suggest that a missense substitution within this domain may affect protein function. In summary, this variant is a rare missense change that has been reported in affected individuals and shown to impair BRCA2 protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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