rs878853614
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000059.4(BRCA2):c.8881G>A(p.Gly2961Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,304 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 Uncertain significance (★★).
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.8881G>A | p.Gly2961Ser | missense_variant | 22/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8881G>A | p.Gly2961Ser | missense_variant | 22/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461304Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726930
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2019 | Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast cancer (Cecener 2019); Also known as 9109G>A; This variant is associated with the following publications: (PMID: 31706072, 29310832) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 07, 2016 | Variant summary: The c.8881G>A (p.Gly2961Ser) in BRCA2 gene is a missense change that involves a non-conserved nucleotide and 3/4 in silico tools predict benign outcome. The variant is located within the tower domain, however no functional studies confirming the impact of the variant on the protein function were published at the time of evaluation. The variant is absent from the large control population dataset of ExAC. The variant has not, to our knowledge, been reported in affected individuals in the literature, but was cited as VUS by several reputable databases/clinical laboratories. Lastly, this variant was identified in an internal specimen, undergoing genetic testing, together with c.3228_3229delAG in BRCA1 gene. Taking together, the variant was classified as VUS until more data become available. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2023 | The p.G2961S variant (also known as c.8881G>A), located in coding exon 21 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8881. The glycine at codon 2961 is replaced by serine, an amino acid with similar properties. This alteration has been reported in 1/898 unrelated Greek families referred for genetic testing of BRCA1 and BRCA2 and was classified as a variant of unknown significance by the authors (Apessos A et al. Cancer Genet, 2018 01;220:1-12). Another study reported that this alteration was observed in at least one of 603 Turkish patients undergoing BRCA1/2 genetic testing due to their diagnosis of breast cancer (Cecener G et al. Cancer Genet. 2020 Jan;240:23-32). 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 | May 09, 2023 | This missense variant replaces glycine with serine at codon 2961 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 breast cancer (PMID: 31706072) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001113). 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. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 30, 2023 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2961 of the BRCA2 protein (p.Gly2961Ser). 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, 31706072). ClinVar contains an entry for this variant (Variation ID: 236923). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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. - |
Breast carcinoma Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 16, 2021 | Invasive Ductal Carcinoma - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at