Submissions for variant NM_000059.4(BRCA2):c.7310T>A (p.Ile2437Asn)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002380057	SCV002669733	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-12	criteria provided, single submitter	clinical testing	The p.I2437N variant (also known as c.7310T>A), located in coding exon 13 of the BRCA2 gene, results from a T to A substitution at nucleotide position 7310. The isoleucine at codon 2437 is replaced by asparagine, an amino acid with dissimilar 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003530251	SCV004320011	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-04	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 1758261). 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. 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. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 2437 of the BRCA2 protein (p.Ile2437Asn).
All of Us Research Program, National Institutes of Health	RCV004005747	SCV004827733	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with asparagine at codon 2437 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 not been reported in individuals affected with BRCA2-related disorders in the literature. 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.