Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Michigan Medical Genetics Laboratories, |
RCV000211033 | SCV000195937 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2014-11-03 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000774931 | SCV000908988 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-29 | criteria provided, single submitter | clinical testing | This missense variant replaces phenylalanine with leucine at codon 1734 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Invitae | RCV001368647 | SCV001565050 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2022-06-30 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1734 of the BRCA1 protein (p.Phe1734Leu). This variant is not present in population databases (gnomAD no frequency). 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: 12496477, 30209399). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 225711). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 21520333). |
Ambry Genetics | RCV000774931 | SCV002641982 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-10-11 | criteria provided, single submitter | clinical testing | The p.F1734L variant (also known as c.5202T>G), located in coding exon 18 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5202. The phenylalanine at codon 1734 is replaced by leucine, an amino acid with highly similar properties. Based on internal structural analysis, F1734L decreases the structure stability (Wu Q et al. Mol Cell, 2016 Feb;61:434-448). 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 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Myriad Genetics, |
RCV000211033 | SCV004018646 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2023-06-02 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30209399, 35196514]. |
Brotman Baty Institute, |
RCV000211033 | SCV001237914 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |