rs80358667
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000059.4(BRCA2):c.4316C>A(p.Ala1439Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000501 in 1,595,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1439S) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.4316C>A | p.Ala1439Asp | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.4316C>A | p.Ala1439Asp | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152048Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000206 AC: 5AN: 242828Hom.: 0 AF XY: 0.00000759 AC XY: 1AN XY: 131678
GnomAD4 exome AF: 0.00000416 AC: 6AN: 1443372Hom.: 0 Cov.: 35 AF XY: 0.00000280 AC XY: 2AN XY: 714666
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74378
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 18, 2011 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 30, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Oct 29, 2001 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Jan 22, 2020 | 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 - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 25, 2022 | 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. - |
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 08, 2016 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 30, 2023 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 11, 2023 | See Variant Classification Assertion Criteria. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 22, 2024 | 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. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at