Submissions for variant NM_000059.4(BRCA2):c.3070A>G (p.Ile1024Val)

dbSNP: rs876659687

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217862	SCV000276407	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-12	criteria provided, single submitter	clinical testing	The p.I1024V variant (also known as c.3070A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3070. The isoleucine at codon 1024 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Grigore LG et al. Curr Issues Mol Biol, 2024 May;46:4630-4645; Stella S et al. Genes (Basel), 2024 Jul;15:). 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. Based on the available evidence, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590483	SCV000694661	uncertain significance	not provided	2016-07-22	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.3070A>G (p.Ile1024Val) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). Ile1024 is not located in the BRC repeat region but is not in a known functional domain of the breast cancer type 2 susceptibility protein. This variant was absent in 120298 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000217862	SCV001358898	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1024 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 ovarian cancer (PMID: 31556562). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853584	SCV002111070	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1024 of the BRCA2 protein (p.Ile1024Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 232307). 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	RCV000217862	SCV003850356	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).
Mayo Clinic Laboratories, Mayo Clinic	RCV000590483	SCV004226420	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing	BP5, PM2