rs786202836
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_000059.4(BRCA2):āc.5126A>Cā(p.Asp1709Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 1,431,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. D1709G) 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 -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.5126A>C | p.Asp1709Ala | missense_variant | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5126A>C | p.Asp1709Ala | missense_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.4757A>C | p.Asp1586Ala | missense_variant | 11/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.5126A>C | non_coding_transcript_exon_variant | 10/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000441 AC: 1AN: 226644Hom.: 0 AF XY: 0.00000814 AC XY: 1AN XY: 122868
GnomAD4 exome AF: 0.00000349 AC: 5AN: 1431154Hom.: 0 Cov.: 44 AF XY: 0.00000423 AC XY: 3AN XY: 709990
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3Benign:1
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). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 05, 2023 | The p.D1709A variant (also known as c.5126A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 5126. The aspartic acid at codon 1709 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Santonocito C et al. Cancers (Basel), 2020 May;12:; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). This amino acid position is not well 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 22, 2022 | This missense variant replaces aspartic acid with alanine at codon 1709 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 three individuals affected with breast or ovarian cancer (PMID: 32438681, 35402282) and in one unaffected individual (PMID: 35944511). This variant has been identified in 1/226644 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 16, 2021 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 29, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 29, 2023 | The frequency of this variant in the general population, 0.0000044 (1/226644 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 35402282 (2022), 32438681 (2020)). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 11, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal or family history of breast, ovarian and/or prostate cancer (PMID: 32438681, 35402282, 35534704, 37842866); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5354A>C; This variant is associated with the following publications: (PMID: 32438681, 35944511, 35402282, 32377563, 29884841, 31853058, 37842866, 35534704) - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 28, 2023 | This missense variant replaces aspartic acid with alanine at codon 1709 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 an individual affected with ovarian cancer (PMID: 32438681). This variant has been identified in 1/226644 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. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at