13-32379318-G-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000059.4(BRCA2):c.8756G>T(p.Gly2919Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000059.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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BRCA2 | ENST00000380152.8 | c.8756G>T | p.Gly2919Val | missense_variant, splice_region_variant | Exon 22 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.8387G>T | p.Gly2796Val | missense_variant, splice_region_variant | Exon 22 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*814G>T | splice_region_variant, non_coding_transcript_exon_variant | Exon 21 of 26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259 | n.*814G>T | 3_prime_UTR_variant | Exon 21 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152068Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461234Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 726952
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152068Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74280
ClinVar
Submissions by phenotype
not provided Uncertain:3
The BRCA2 c.8756G>T (p.Gly2919Val) variant has been reported in the published literature in individuals with breast cancer as well as reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)), and in a cohort of individuals referred for hereditary breast/ovarian cancer testing (PMID: 31853058 (2020)). Computational studies have reported conflicting findings that this variant may have a deleterious or neutral effect on BRCA2 function (PMID: 19043619 (2008), 24817641 (2014)). This variant 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. -
The BRCA2 c.8756G>T; p.Gly2919Val variant (rs80359131), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 52673). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.225). Due to limited information, the clinical significance of this variant is uncertain at this time. -
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with a personal and family history of cancer undergoing multi-gene panel testing (PMID: 31853058); Also known as 8984G>T; This variant is associated with the following publications: (PMID: 21523855, 24817641, 19043619, 31131967, 31853058, 12228710, 29884841, 32377563, 36922933) -
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
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BRCA2-related cancer predisposition Uncertain:2
This missense variant replaces glycine with valine at codon 2919 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. -
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
The p.G2919V variant (also known as c.8756G>T), located in coding exon 21 of the BRCA2 gene, results from a G to T substitution at nucleotide position 8756. The glycine at codon 2919 is replaced by valine, an amino acid with dissimilar properties. In a study utilizing a bioinformatics method that integrates information about protein sequence, conservation, and structure in a protein likelihood ratio, the effect of this alteration was predicted neutral (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). 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. -
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not specified Uncertain:1
Variant summary: BRCA2 c.8756G>T (p.Gly2919Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250484 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8756G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19043619, 21523855). ClinVar contains an entry for this variant (Variation ID: 52673). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Familial cancer of breast Uncertain:1
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Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2919 of the BRCA2 protein (p.Gly2919Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 52673). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be tolerated (PMID: 19043619). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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