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

gnomAD frequency: 0.00001  dbSNP: rs80358667

Total submissions: 12

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	2024-01-22	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 domain 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, predominantly at a frequency of 0.00015 within the Latino subpopulation in the gnomAD database. 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). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 28477318, 22476429, 25136594, 17925560). ClinVar contains an entry for this variant (Variation ID: 37893). 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].
Labcorp Genetics (formerly Invitae), Labcorp	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).
All of Us Research Program, National Institutes of Health	RCV000031474	SCV004845662	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
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