ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4316C>A (p.Ala1439Asp)

gnomAD frequency: 0.00001  dbSNP: rs80358667
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131416 SCV000186394 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-25 criteria provided, single submitter clinical testing The p.A1439D variant (also known as c.4316C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 4316. The alanine at codon 1439 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been detected in several cohorts of patients with a family history of breast and ovarian cancer (Vogel KJ et al. J. Clin. Oncol. 2007 Oct;25(29):4635-14; Lu W et al. Fam. Cancer. 2012 Sep;11(3):381-5; Ruiz A et al. Biomed. Res. Int. 2014 Jun;2014:542541; Gabaldó Barrios X et al. Fam. Cancer 2017 Oct;16(4):477-489). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000656795 SCV000210334 likely benign not provided 2023-07-11 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656795 SCV000600583 uncertain significance not provided 2023-03-30 criteria provided, single submitter clinical testing In the published literature, the variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMIDs: 22476429 (2012), 25136594 (2014) and 28477318 (2017)). The frequency of this variant in the general population, 0.00015 (5/33030 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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.
Color Diagnostics, LLC DBA Color Health RCV000131416 SCV000903865 likely benign Hereditary cancer-predisposing syndrome 2016-03-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212234 SCV001363145 uncertain significance not specified 2022-08-29 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4316C>A (p.Ala1439Asp) results in a non-conservative amino acid change located in the BRCA2 repeat of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 242828 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4316C>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Gabaldo Barrios_2017, Lu_2012, Ruiz_2014, Vogel_2007 etc.). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.4327C>T, p.R1443X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after (VUS=7, Likely benign=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Division of Medical Genetics, University of Washington RCV000031474 SCV001434319 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2020-01-22 criteria provided, single submitter clinical testing This variant has been reported in the literature in individuals with a personal and/or family history of breast and ovarian cancer (Vogel 2007, Ruiz 2014, Gabaldo Barrios 2017). This variant has an overall allele frequency of 0.000017 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3
Baylor Genetics RCV000031474 SCV001481401 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2020-08-30 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV001316319 SCV001506929 likely benign Hereditary breast ovarian cancer syndrome 2024-01-29 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000131416 SCV003850411 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).
Sharing Clinical Reports Project (SCRP) RCV000031474 SCV000054079 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2011-10-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031474 SCV000146406 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2001-10-29 no assertion criteria provided clinical testing

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