Submissions for variant NM_000059.4(BRCA2):c.3526G>A (p.Val1176Ile)

gnomAD frequency: 0.00001  dbSNP: rs80358602

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221053	SCV000278489	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-19	criteria provided, single submitter	clinical testing	The p.V1176I variant (also known as c.3526G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 3526. The valine at codon 1176 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health	RCV000221053	SCV000688812	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637690	SCV000759161	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-25	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 1176 of the BRCA2 protein (p.Val1176Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 22713736). ClinVar contains an entry for this variant (Variation ID: 126016). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000221053	SCV003846679	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477487	SCV004219591	uncertain significance	not provided	2023-07-28	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in several individuals in a hereditary cancer testing cohort (PMID: 31853058 (2020)). It has also been observed in an individual with breast cancer and in a control individual in a breast cancer association study (PMID: 33471991 (2021), ). In addition, this variant has been reported to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.0000066 (1/152190 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
All of Us Research Program, National Institutes of Health	RCV004804106	SCV005424386	uncertain significance	BRCA2-related cancer predisposition	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1176 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. This variant does not impact cell viability or drug sensitivity in Brca2-deficient mouse embryonic stem cells (PMID: 37922907). In a large breast cancer case-control meta-analysis, this variant was reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008075). This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.050 and 0.745, respectively (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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113189	SCV000146253	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113189	SCV000297520	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-11-07	no assertion criteria provided	clinical testing