rs80359094
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6
The NM_000059.4(BRCA2):c.8452G>A(p.Val2818Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 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. V2818F) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8452G>A | p.Val2818Ile | missense_variant | 19/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8452G>A | p.Val2818Ile | missense_variant | 19/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251400Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135886
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461572Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727134
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Dec 23, 2003 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces valine with isoleucine at codon 2818 of the BRCA2 protein. This variant is also known as 8680G>A in the literature. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 16847550, 16760289) and an individual with an unspecified cancer (PMID: 32438681). This variant has been identified in 1/251400 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, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 28, 2015 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 26, 2022 | The frequency of this variant in the general population, 0.000011 (2/181718 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been reported in a family affected with breast and/or ovarian cancer (PMID: 16847550 (2006)) and in individuals with a personal history of breast cancer (PMIDs: 32658311 (2021) and 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)) or an unspecified cancer type (PMID: 32438681 (2020)). In addition, this variant was predicted to be neutral using a computational model specific for BRCA2 (PMID: 19043619 (2008)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2017 | This variant is denoted BRCA2 c.8452G>A at the cDNA level, p.Val2818Ile (V2818I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant, also denoted BRCA2 c.8680G>A by alternate nomenclature, has been identified in at least one breast and/or ovarian cancer family (Capalbo 2006). BRCA2 Val2818Ile was not observed at a significant frequency in large population cohorts (Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val2818Ile is located in the DNA binding domain (Yang 2002). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Val2818Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 02, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 09, 2024 | ACMG codes applied following ENIGMA VCEP rules: BP4, PM2_SUP - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 15, 2023 | This missense variant replaces valine with isoleucine at codon 2818 of the BRCA2 protein. This variant is also known as 8680G>A in the literature. 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 individuals affected with breast and/or ovarian cancer (PMID: 16847550, 16760289, 32658311, 34658299) and an individual affected with an unspecified cancer (PMID: 32438681). This variant has been identified in 1/251400 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 | Oct 11, 2023 | The p.V2818I variant (also known as c.8452G>A), located in coding exon 18 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8452. The valine at codon 2818 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been identified in multiple hereditary breast and/or ovarian cancer families (Capalbo C et al. Ann. Oncol., 2006 Jun;17 Suppl 7:vii34-40; Giannini G et al. Breast Cancer Res Treat. 2006 Nov; 100(1):83-91). This alteration was also seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295).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. - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 02, 2024 | Variant summary: BRCA2 c.8452G>A (p.Val2818Ile) results in a conservative amino acid change located in the BRCA2, OB2 domain (IPR048262) of the encoded protein sequence. Four 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 251400 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8452G>A has been reported in the literature as a VUS in settings of multigene panel or BRCA1/2 testing among individuals affected with a variety of cancers to include breast/ovarian/colorectal (example, Akcay_2021, Santonocito_2020, Bisgin_2022) and in earlier reports of individuals undergoing testing for breat/ovarian cancer (example, Capalbo_2006, Giannini_2006). These report(s) 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: 32658311, 35753294, 16760289, 16847550, 34658299, 32438681). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=6; likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at