Submissions for variant NM_000059.4(BRCA2):c.4199A>G (p.His1400Arg)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002327814	SCV002627088	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	The p.H1400R variant (also known as c.4199A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4199. The histidine at codon 1400 is replaced by arginine, an amino acid with highly similar properties. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003094579	SCV003333058	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-18	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1400 of the BRCA2 protein (p.His1400Arg). 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: 1738603). 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. 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	RCV002327814	SCV003848760	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	RCV003234591	SCV003932349	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-15	criteria provided, single submitter	clinical testing	a variant of uncertain significance was detected in the BRCA2 gene (c.4199A>G). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1400 of the BRCA2 protein (p.His1400Arg). This variant is not present in population databases (gnomAD no frequency) nor in our local database . This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This alteration is predicted to be tolerated by in silico analysis based on predictions from PolyPhen , BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MutationTaster, PrimateAI ,SIFT , DEOGEN2, MVP and MutationAssessor. 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.