Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000509942 | SCV000608205 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-10-30 | criteria provided, single submitter | clinical testing | The p.V1653M variant (also known as c.4957G>A), located in coding exon 14 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4957. The valine at codon 1653 is replaced by methionine, an amino acid with highly similar properties. This alteration has been identified in multiple breast and/or ovarian cancer cohorts (Hirotsu Y et al. Mol Genet Genomic Med. 2015 Mar;3:121-9; Nakagomi H et al. Cancer Sci. 2018 Feb;109:453-461). This alteration has mixed results in various functional assays including a transcription activation assay where it is non-functional; intermediate effects in binding activity and specificity, and WT-like effects in a yeast-based small colony-forming assay (Coyne RS et al. Cancer Biol. Ther. 2004 May;3:453-7; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Fernandes VC et al. J Biol Chem. 2019 04;294:5980-5992). 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. |
| Invitae | RCV001296485 | SCV001485451 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2021-10-18 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15004537, 20516115, 28781887). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 55331). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9333265). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 1653 of the BRCA1 protein (p.Val1653Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. |
| Breast Cancer Information Core |
RCV000112435 | SCV000145223 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 1997-02-15 | no assertion criteria provided | clinical testing |