Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420879 | SCV001623302 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2021-04-18 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.4957G>T (p.Val1653Leu) results in a conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. However, a different substitution at the same codon, namely BRCA1, p.V1653M has been reported to impact BRCA1 function suggestive of the functional relevance of this residue. The variant was absent in 250924 control chromosomes. c.4957G>T has been reported in the literature in at-least three individuals of Japanese ancestry affected with Hereditary Breast And Ovarian Cancer Syndrome and at-least one reportedly unaffected Japanese woman control, although the possibility of breast cancer in this control subject cannot be ruled out (example, Hirotsu_2015, Nakagomi_2018, Momozawa_2018, Hirotsu_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of normal HDR activity (example Findlay_2018). In a cross sectional review of literature, this variant was initially classified as a "VUS" and has recently been re-classified as "Likely Pathogenic" citing the functional study utilized in the context of this evaluation (Hirotsu_2015, Hirotsu_2020, Findlay_2018). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Ambry Genetics | RCV003339468 | SCV004058417 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-13 | criteria provided, single submitter | clinical testing | The p.V1653L variant (also known as c.4957G>T), located in coding exon 14 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4957. The valine at codon 1653 is replaced by leucine, an amino acid with highly similar properties. This alteration was detected in a cohort of 135 Japanese breast and/or ovarian cancer patients (Hirotsu Y et al. Mol Genet Genomic Med, 2015 Mar;3:121-9). One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Brotman Baty Institute, |
RCV001077861 | SCV001243856 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro | ||
| Laboratory for Genotyping Development, |
RCV003160607 | SCV002758200 | pathogenic | Gastric cancer | 2021-07-01 | no assertion criteria provided | research |