Submissions for variant NM_000059.4(BRCA2):c.4372C>A (p.His1458Asn)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002706512	SCV003001895	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1458 of the BRCA2 protein (p.His1458Asn). 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).
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157227	SCV003850458	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).
Ambry Genetics	RCV003157227	SCV005027052	likely benign	Hereditary cancer-predisposing syndrome	2023-11-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV004765554	SCV005377396	uncertain significance	not provided	2023-11-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 4600C>A