13-32339436-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6
The NM_000059.4(BRCA2):c.5081G>A(p.Arg1694Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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. R1694T) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.5081G>A | p.Arg1694Lys | 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.5081G>A | p.Arg1694Lys | missense_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000428 AC: 1AN: 233448Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 126536
GnomAD4 exome AF: 6.95e-7 AC: 1AN: 1439780Hom.: 0 Cov.: 46 AF XY: 0.00 AC XY: 0AN XY: 714144
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2023 | The p.R1694K variant (also known as c.5081G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5081. The arginine at codon 1694 is replaced by lysine, an amino acid with highly similar properties. 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. - |
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). - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 12, 2016 | This sequence change replaces arginine with lysine at codon 1694 of the BRCA2 protein (p.Arg1694Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The lysine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jun 25, 2021 | The BRCA2 c.5081G>A variant is classified as Likely Benign (BP1, BP4) The BRCA2 c.5081G>A variant is a single nucleotide change in the BRCA2 gene, which is predicted to change the amino acid arginine at position 1694 in the protein to lysine. Disease causing variants in BRCA2 are predominantly trucating variants and this variant is a missense variant (BP1). Multiple lines of computational evidence suggest this variant has no impact on the gene or gene product (BP4). The variant has been reported as Uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 409591). It has not been reported in dbSNP or HGMD. - |
Familial cancer of breast Benign:1
Likely benign, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 09, 2024 | ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at