Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000043719 | SCV000071732 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-09-25 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs80358396, gnomAD 0.005%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 338 of the BRCA2 protein (p.Ala338Thr). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22425665, 30199306, 34597585). ClinVar contains an entry for this variant (Variation ID: 51048). 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. 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. |
Ambry Genetics | RCV000509731 | SCV000608018 | likely benign | Hereditary cancer-predisposing syndrome | 2019-03-13 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: 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. |
Color Diagnostics, |
RCV000509731 | SCV000688688 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-06 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with threonine at codon 338 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three individuals affected with breast and/or ovarian cancer and five unaffected individuals (PMID: 22425665, 30199306, 33471991; Leiden Open Variation Database DB-ID BRCA2_001878). This variant also has been reported in two multifactorial analyses with co-occurrence and family history likelihood ratios for pathogenicity of 1.1022 and 3.304, respectively (PMID: 31131967) and tumor pathology and co-segregation likelihood ratios for pathogenicity of 0.58 and 0.33877369, respectively (PMID: 34597585). This variant has been identified in 7/246458 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. |
Mendelics | RCV000043719 | SCV000838751 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759572 | SCV000888972 | uncertain significance | not provided | 2023-08-23 | criteria provided, single submitter | clinical testing | In the published literature, this variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 34597585 (2021), 34196900 (2021), 30199306 (2018), 22425665 (2012)). The frequency of this variant in the general population, 0.000053 (6/112294 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. |
Mendelics | RCV000112875 | SCV001138986 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
RCV001111640 | SCV001269210 | uncertain significance | Fanconi anemia complementation group D1 | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Illumina Laboratory Services, |
RCV000112875 | SCV001269211 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001280581 | SCV001467788 | uncertain significance | not specified | 2020-12-15 | criteria provided, single submitter | clinical testing | Variant summary: BRCA2 c.1012G>A (p.Ala338Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 246458 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1012G>A has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (Tazzite_2012, Abulkhair_2018). These reports 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. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (6x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance. |
Gene |
RCV000759572 | SCV002028983 | uncertain significance | not provided | 2022-06-06 | criteria provided, single submitter | clinical testing | Identified in individuals with a personal or family history of breast and/or ovarian cancer (Tazzite 2012, Gabaldo Barrios 2017, Abulkhair 2018, Caputo 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 1240G>A; This variant is associated with the following publications: (PMID: 22425665, 30199306, 31131967, 28477318, 34597585) |
University of Washington Department of Laboratory Medicine, |
RCV000509731 | SCV003849776 | likely benign | Hereditary cancer-predisposing syndrome | 2023-03-23 | criteria provided, single submitter | curation | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). |
KCCC/NGS Laboratory, |
RCV000112875 | SCV003932706 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2023-06-06 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine with threonine at codon 338 of the BRCA2 protein (p.Ala338Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs80358396, ExAC 0.008%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22425665, 30199306). ClinVar contains an entry for this variant (Variation ID: 51048). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. Pathogenic mutations in the BRCA2 gene cause hereditary breast/ovarian cancer syndrome. |
Ce |
RCV000759572 | SCV004033241 | uncertain significance | not provided | 2023-07-01 | criteria provided, single submitter | clinical testing | BRCA2: PM2, BP4 |
Breast Cancer Information Core |
RCV000112875 | SCV000145805 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2002-05-29 | no assertion criteria provided | clinical testing | |
BRCAlab, |
RCV000112875 | SCV004244136 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2020-03-02 | no assertion criteria provided | clinical testing |