Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000045811 | SCV000073824 | pathogenic | Hereditary breast ovarian cancer syndrome | 2025-01-15 | criteria provided, single submitter | clinical testing | This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 31 of the BRCA2 protein (p.Trp31Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22678057; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52830). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 16793542, 20215541, 22194698, 22678057, 24285729). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Trp31 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11149425, 30093976, 30410870, 31742824, 32778078; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV000565952 | SCV000661412 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-31 | criteria provided, single submitter | clinical testing | The p.W31C variant (also known as c.93G>T), located in coding exon 2 of the BRCA2 gene, results from a G to T substitution at nucleotide position 93. The tryptophan at codon 31 is replaced by cysteine, an amino acid with highly dissimilar properties. Multiple in vitro functional studies have reported that p.W31C impairs BRCA2 homologous recombination (HR) function and PALB2 binding activity (Siaud N et al. PLoS Genet., 2011 Dec;7:e1002409; Al Abo M et al. Cancer Res., 2014 Feb;74:797-807; Oliver AW et al. EMBO Rep., 2009 Sep;10:990-6; Xia B et al. Mol. Cell, 2006 Jun;22:719-29; Biswas K et al. Hum. Mol. Genet., 2012 Sep;21:3993-4006; Shimelis H et al. Cancer Res., 2017 06;77:2789-2799; Mesman RLS et al. Genet. Med., 2018 Jul; Caleca L et al. Front Oncol. 2018 Oct;8:480; Ikegami M et al. Nat Commun. 2020 May;11(1):2573; Thomassen M et al. Hum Mutat. 2022 Dec;43(12):1921-1944). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Breast Cancer Information Core |
RCV000113126 | SCV000146157 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | no assertion criteria provided | clinical testing |