Submissions for variant NM_000059.4(BRCA2):c.8452G>A (p.Val2818Ile)

gnomAD frequency: 0.00001  dbSNP: rs80359094

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045523	SCV000073536	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000212275	SCV000210472	uncertain significance	not provided	2017-11-22	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000166574	SCV000217376	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-11	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000113935	SCV000488099	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166574	SCV000689128	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193320	SCV001362071	uncertain significance	not specified	2024-01-02	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212275	SCV001469726	uncertain significance	not provided	2022-07-26	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193320	SCV002551819	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460619	SCV004216169	uncertain significance	Familial cancer of breast	2023-05-02	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV003460619	SCV004543919	uncertain significance	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP4, PM2_SUP
All of Us Research Program, National Institutes of Health	RCV000113935	SCV004846024	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing	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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113935	SCV000147367	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000113935	SCV004243819	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing