rs770479195
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_000059.4(BRCA2):āc.7A>Gā(p.Ile3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,650 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7A>G | p.Ile3Val | missense_variant | 2/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7A>G | p.Ile3Val | missense_variant | 2/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251358Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135862
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461436Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727050
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74366
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2023 | This missense variant replaces isoleucine with valine at codon 3 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 been identified in 2/251358 chromosomes 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2023 | The p.I3V variant (also known as c.7A>G), located in coding exon 1 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7. The isoleucine at codon 3 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in Brazilian breast cancer cohorts (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is poorly conserved in available vertebrate species, and valine is the reference amino acid in multiple 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 | curation | Sema4, Sema4 | Mar 17, 2022 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces isoleucine with valine at codon 3 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 been identified in 2/251358 chromosomes 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as BRCA2 235A>G; This variant is associated with the following publications: (PMID: 20167696) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 28, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 14, 2024 | Variant summary: BRCA2 c.7A>G (p.Ile3Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251358 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7A>G has been reported in the literature in individuals with a personal and/or family history of breast cancer (e.g., Sandoval_2021, Guindalini_2022, deOliveira_2022, Gifoni_2022), however without strong evidence for causality (e.g., lack of co-segregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35957908, 35264596, 20167696, 33606809, 35534704, 16683254). ClinVar contains an entry for this variant (Variation ID: 231466). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3 of the BRCA2 protein (p.Ile3Val). This variant is present in population databases (rs770479195, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 21520333, 35264596; Invitae). ClinVar contains an entry for this variant (Variation ID: 231466). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at