Submissions for variant NM_000059.4(BRCA2):c.4785G>T (p.Gln1595His)

dbSNP: rs1060502499

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476642	SCV000549885	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-09-06	criteria provided, single submitter	clinical testing	In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. This sequence change replaces glutamine with histidine at codon 1595 of the BRCA2 protein (p.Gln1595His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine.
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157555	SCV003852094	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357236	SCV001552641	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Gln1595His variant was not identified in the literature nor was it identified in the LOVD 3.0 and UMD-LSDB databases. The variant was identified in dbSNP (ID: rs1060502499) “With Uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gln1595 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant His impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.