chr13-32379337-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000059.4(BRCA2):āc.8775G>Cā(p.Gln2925His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,516 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q2925P) has been classified 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8775G>C | p.Gln2925His | missense_variant | 22/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8775G>C | p.Gln2925His | missense_variant | 22/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250674Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135522
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461516Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727056
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 20, 2023 | In the published literature, this variant has been reported in individuals with pancreatic cancer (PMID: 25479140 (2015)), and breast cancer (PMID: 28202063 (2017), 31706072 (2020)). In a large breast cancer association study, this variant was reported in a healthy individual (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA2). Experimental evidence suggests this variant is not detrimental to homology directed DNA repair function in vitro (PMID: 29394989 (2018)). The frequency of this variant in the general population, 0.000004 (1/250674 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | BRCA2: PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 28, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies are inconclusive: homology directed DNA repair activity in both the indeterminate and benign ranges (Guidugli et al., 2018; Hart et al., 2019); Also known as 9003G>C; This variant is associated with the following publications: (PMID: 19043619, 29394989, 31706072, 28202063, 30675319, 25479140, 29884841, 12228710) - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 21, 2012 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 04, 2019 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 2925 of the BRCA2 protein (p.Gln2925His). This variant is present in population databases (rs80359136, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer or pancreatic cancer (PMID: 25479140, 28202063, 31706072). ClinVar contains an entry for this variant (Variation ID: 52678). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29394989). 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