ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1012G>A (p.Ala338Thr)

gnomAD frequency: 0.00003  dbSNP: rs80358396
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Total submissions: 15
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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, LLC DBA Color Health 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, Illumina 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, Illumina 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, LabCorp 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.
GeneDx 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, University of Washington 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, Kuwait Cancer Control Center 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.
CeGaT Center for Human Genetics Tuebingen RCV000759572 SCV004033241 uncertain significance not provided 2023-07-01 criteria provided, single submitter clinical testing BRCA2: PM2, BP4
Breast Cancer Information Core (BIC) (BRCA2) RCV000112875 SCV000145805 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2002-05-29 no assertion criteria provided clinical testing
BRCAlab, Lund University RCV000112875 SCV004244136 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2020-03-02 no assertion criteria provided clinical testing

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