Submissions for variant NM_000059.4(BRCA2):c.5707A>G (p.Ile1903Val)

dbSNP: rs431825333

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220000	SCV000276757	uncertain significance	Hereditary cancer-predisposing syndrome	2015-07-13	criteria provided, single submitter	clinical testing	The p.I1903V variant (also known as c.5707A>G or 5935A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5707. The isoleucine at codon 1903 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage of 6503 at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0007% (greater than 150000 alleles tested) in our clinical cohort. 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 p.I1903V remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759628	SCV000889075	uncertain significance	not provided	2018-01-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791836	SCV000931100	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-13	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 1903 of the BRCA2 protein (p.Ile1903Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333, 30287823). ClinVar contains an entry for this variant (Variation ID: 232588). 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	RCV000220000	SCV003849032	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).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003991026	SCV004808351	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-04-03	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 1903 of the BRCA2 protein (p.Ile1903Val).This amino acid position is not well conserved .This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333, 30287823). ClinVar contains an entry for this variant (Variation ID: 232588). In addition, this alteration is predicted to be tolerated by in silico analysis. 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.