Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000222813 | SCV000274714 | likely benign | Hereditary cancer-predisposing syndrome | 2022-01-05 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Labcorp Genetics |
RCV000552479 | SCV000635619 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2024-01-28 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2645 of the BRCA2 protein (p.Arg2645Gly). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 22505045, 27356891, 32853339, 34597585). ClinVar contains an entry for this variant (Variation ID: 230994). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Studies have shown that this missense change does not affect mRNA splicing (PMID: 22505045). 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. |
Color Diagnostics, |
RCV000222813 | SCV000683917 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-17 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glycine at codon 2645 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 27356891), an individual affected with prostate cancer (PMID: 32853339), and in a multifactorial analysis with family history, pathology and segregation likelihood ratios for pathogenicity of 0.24, 0.05, and 2.93, respectively (PMID: 34597585). This variant has been identified in 3/251304 chromosomes 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. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759664 | SCV000889141 | uncertain significance | not provided | 2021-08-26 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193806 | SCV001362934 | uncertain significance | not specified | 2023-10-23 | criteria provided, single submitter | clinical testing | Variant summary: BRCA2 c.7933A>G (p.Arg2645Gly) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 254522 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7933A>G has been reported in the literature in individuals affected with Hereditary Breast and/or Ovarian Cancer Syndrome (e.g. Caputo_2021), colorectal cancer (e.g. Dobbins_2016), or prostate cancer (e.g. Darst_2021) without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22505045, 34597585, 32853339, 27356891, 35260348). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. |
All of Us Research Program, |
RCV003997876 | SCV004845574 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2023-12-13 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glycine at codon 2645 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 27356891), an individual affected with prostate cancer (PMID: 32853339), and in a multifactorial analysis with family history, pathology and segregation likelihood ratios for pathogenicity of 0.24, 0.05, and 2.93, respectively (PMID: 34597585). This variant has been identified in 3/251304 chromosomes 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. |