Submissions for variant NM_000059.4(BRCA2):c.6196G>A (p.Val2066Ile)

gnomAD frequency: 0.00004  dbSNP: rs397507365

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132349	SCV000187438	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-24	criteria provided, single submitter	clinical testing	The p.V2066I variant (also known as c.6196G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6196. The valine at codon 2066 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was identified amongst a cohort of 427 patients undergoing genetic testing due to a diagnosis of prostate cancer (Giri VN et al. JCO Precis Oncol, 2022 May;6:e2200234). This alteration was classified as likely benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat, 2019 09;40:1557-1578). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031605	SCV000267791	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476966	SCV000549676	likely benign	Hereditary breast ovarian cancer syndrome	2024-11-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000588799	SCV000564789	likely benign	not provided	2019-11-05	criteria provided, single submitter	clinical testing	Not observed 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; This variant is associated with the following publications: (PMID: 26155992, 31131967)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855632	SCV000694946	uncertain significance	not specified	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6196G>A (p.Val2066Ile) results in a conservative amino acid change located in the BRCA2 repeat region (IPR002093) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 152194 control chromosomes, exclusively found within the African/African American subpopulation (i.e. 5/41448 alleles; frequency: 0.00012) in the gnomAD v3.1 database, genomes dataset. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6196G>A has been reported in the literature in a prostate cancer patient, however without strong evidence for causality (e.g., Giri_2022), as well as detected in a tumor sample from a patient with cervical squamous cell carcinoma, but without corresponding testing of germline DNA and without causative evidence related to the disease (e.g., Muller_2015). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. A co-occurrence with another pathogenic variant has been reported (BRCA2 c.7558C>T (p.Arg2520X), in an internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A recent multifactorial likelihood analysis predicted this variant to be likely benign (Parsons_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31294896, 35666082, 26155992, 31112341, 31131967). Nine ClinVar submitters (evaluation after 2014) have cited the variant, with 6 submitters classifying the variant as uncertain significance, and 3 submitters classifying the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000031605	SCV000785801	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588799	SCV000889087	uncertain significance	not provided	2017-12-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132349	SCV000906132	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2066 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 (PMID: 35666082). A multifactorial analysis using co-occurrence with another pathogenic variant and family history likelihood ratios has determined that this variant is unlikely to be disease-causing (PMID: 31131967). This variant has not been identified 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.
Sema4, Sema4	RCV000132349	SCV002536208	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-20	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132349	SCV003852309	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000031605	SCV004846717	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2066 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 (PMID: 35666082). A multifactorial analysis using co-occurrence with another pathogenic variant and family history likelihood ratios has determined that this variant is unlikely to be disease-causing (PMID: 31131967). This variant has not been identified 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.
Fulgent Genetics, Fulgent Genetics	RCV005007912	SCV005633948	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-02-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031605	SCV000054212	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-01-09	no assertion criteria provided	clinical testing