13-32326527-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000059.4(BRCA2):c.545A>G(p.Glu182Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.545A>G | p.Glu182Gly | missense_variant | Exon 7 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.176A>G | p.Glu59Gly | missense_variant | Exon 7 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.545A>G | non_coding_transcript_exon_variant | Exon 6 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461548Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727082
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152332Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74498
ClinVar
Submissions by phenotype
not provided Uncertain:2
The BRCA2 c.545A>G (p.Glu182Gly) variant has not been reported in individuals with BRCA2-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 773A>G; This variant is associated with the following publications: (PMID: 32377563, 29884841) -
not specified Uncertain:1
DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.545A>G, in exon 7 that results in an amino acid change, p.Glu182Gly. This sequence change does not appear to have been previously described in individuals with BRCA2-related disorders and has also not been described in the population databases such as ExAC and gnomAD (dbSNP rs786202685). The p.Glu182Gly change affects a highly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu182Gly substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Glu182Gly change remains unknown at this time. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.E182G variant (also known as c.545A>G), located in coding exon 6 of the BRCA2 gene, results from an A to G substitution at nucleotide position 545. The glutamic acid at codon 182 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly 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. -
Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces glutamic acid with glycine at codon 182 of the BRCA2 protein (p.Glu182Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 186091). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at