rs80358908
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000059.4(BRCA2):c.6842G>A(p.Gly2281Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000147 in 1,357,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2281V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.6842G>A | p.Gly2281Glu | missense_variant, splice_region_variant | 12/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.6842G>A | p.Gly2281Glu | missense_variant, splice_region_variant | 12/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000408 AC: 1AN: 244980Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133142
GnomAD4 exome AF: 0.00000147 AC: 2AN: 1357750Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0AN XY: 680324
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 30, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 24, 2021 | The c.6842G>A variant (also known as p.G2281E) is located in coding exon 11 of the BRCA2 gene. The glycine at codon 2281 is replaced by glutamic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. This alteration leads to increased but incomplete skipping of coding exon 11 (also known as exon 12 in the literature; Hujová P et al. Mol Biol Rep, 2019 Jun;46:2877-2884; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). Complete loss of coding exon 11 retains nearly 50% homology-directed DNA repair activity (Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). However, the clinical impact of loss of exon 11 and to what extent exon 11 is lost is uncertain as a different variant that results in incomplete skipping of coding exon 11 was identified in a compound heterozygous state in a patient without apparent Fanconi Anemia (Li L et al. Hum Mutat, 2009 Nov;30:1543-50). This suggests that exon 11 skipping may be dispensable for clinically relevant function at an unknown threshold of loss (Li L et al. Hum Mutat, 2009 Nov;30:1543-50; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico protein prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Nov 13, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2281 of the BRCA2 protein (p.Gly2281Glu). Not observed at significant frequency in large population cohorts (gnomAD). In silico analysis supports that this missense variant does not alter protein structure/function. Observed in an individual with breast cancer (Deuitch et al., 2020). This variant is associated with the following publications: (PMID: 32884827).ClinVar contains an entry for this variant (Variation ID: 926077). This nucleotide position is highly conserved . Studies have shown that this missense change results in the activation of a cryptic splice site (PMID: 32046981). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2022 | Observed in an individual with breast cancer (Deuitch et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7070G>A; Not observed at significant frequency in large population cohorts (gnomAD); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32884827) - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | Studies have shown that this missense change results in the activation of a cryptic splice site in 12 (PMID: 32046981). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 926077). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs80358908, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2281 of the BRCA2 protein (p.Gly2281Glu). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 1 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at