Submissions for variant NM_000059.4(BRCA2):c.2842G>A (p.Val948Ile)

dbSNP: rs1555282901

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637414	SCV000758870	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-15	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 948 of the BRCA2 protein (p.Val948Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast, ovarian and/or colorectal cancer (PMID: 24814045, 27223485). ClinVar contains an entry for this variant (Variation ID: 531247). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV001016754	SCV001177747	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-26	criteria provided, single submitter	clinical testing	The p.V948I variant (also known as c.2842G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 2842. The valine at codon 948 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was seen in a colorectal cancer family and in a hereditary breast and/or ovarian cancer family; however, clinical details were not provided (Garre P et al. Clin. Genet., 2015 Jun;87:582-7; Palmero EI et al. Genet. Mol. Biol., 2016 05;39:210-22). 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.
Color Diagnostics, LLC DBA Color Health	RCV001016754	SCV001353302	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-10	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 948 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual each affected with colorectal cancer or considered at-risk for hereditary breast cancer (PMID: 24814045, 27223485). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001016754	SCV003850179	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).