13-32379337-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).
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8775G>C | p.Gln2925His | missense_variant | Exon 22 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.8406G>C | p.Gln2802His | missense_variant | Exon 22 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*833G>C | non_coding_transcript_exon_variant | Exon 21 of 26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259 | n.*833G>C | 3_prime_UTR_variant | Exon 21 of 25 | 2 | ENSP00000506251.1 |
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
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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. -
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) -
BRCA2: PM2, PS4:Moderate, BP1, BP4, BS3:Supporting -
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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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. -
Hereditary breast ovarian cancer syndrome Uncertain:1
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
Familial cancer of breast;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at