Submissions for variant NM_000059.4(BRCA2):c.4813G>A (p.Val1605Ile)

gnomAD frequency: 0.00026  dbSNP: rs786201175

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162834	SCV000213320	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-26	criteria provided, single submitter	clinical testing	The p.V1605I variant (also known as c.4813G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 4813. The valine at codon 1605 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been investigated using a Bayesian hierarchical model to classify the disease association of missense alterations given pedigree data collected in the high-risk setting and was found to have a strong association with disease (Zhou X et al. J Am Stat Assoc. 2005;100:51-60). This alteration was previously reported in a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med., 2015 Aug;17:630-8). In another study, this variant was reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
GeneDx	RCV000221573	SCV000278853	uncertain significance	not provided	2021-11-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Maxwell 2015); Also known as 5041G>A; This variant is associated with the following publications: (PMID: 25503501, 18418466)
Color Diagnostics, LLC DBA Color Health	RCV000162834	SCV000688898	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637639	SCV000759106	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1605 of the BRCA2 protein (p.Val1605Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or at high risk for breast and ovarian cancer (PMID: 18418466, 21520333, 25503501). ClinVar contains an entry for this variant (Variation ID: 183942). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000221573	SCV000887827	benign	not provided	2023-08-09	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000162834	SCV003852117	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).
Myriad Genetics, Inc.	RCV003315984	SCV004020249	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-10	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.