13-32336703-T-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6
The NM_000059.4(BRCA2):c.2348T>G(p.Val783Gly) 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 1,613,848 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V783A) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.2348T>G | p.Val783Gly | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.2348T>G | p.Val783Gly | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250824Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135654
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461670Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727142
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 12, 2022 | The p.V783G variant (also known as c.2348T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 2348. The valine at codon 783 is replaced by glycine, an amino acid with dissimilar properties. 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 | Mar 15, 2023 | This missense variant replaces valine with glycine at codon 783 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 prostate cancer and in a suspected hereditary breast and ovarian cancer family (PMID: 28259476, 31409081). This variant has also been detected in a breast cancer case-control meta-analysis in 2/53459 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002356) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 0.3997, respectively, (PMID: 31131967). This variant has been identified in 1/250824 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. - |
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 21, 2021 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:1
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 01, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 13, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 08, 2023 | This missense variant replaces valine with glycine at codon 783 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 prostate cancer and in a suspected hereditary breast and ovarian cancer family (PMID: 28259476, 31409081). This variant has also been detected in a breast cancer case-control meta-analysis in 2/53459 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002356) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 0.3997, respectively, (PMID: 31131967). This variant has been identified in 1/250824 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 | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 23, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with prostate cancer (Annala 2017); Also known as 2576T>G; This variant is associated with the following publications: (PMID: 30212499, 31131967, 28259476) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 21, 2022 | Variant summary: BRCA2 c.2348T>G (p.Val783Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250824 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2348T>G has been reported in the literature in at least one individual affected with suspected Hereditary Breast And Ovarian Cancer Syndrome. This reports does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.5266dup/p.Gln1756ProfsX74 and BRCA1 c.5503C>T/p.R1835*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=2, VUS n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 02, 2021 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at