Submissions for variant NM_000059.4(BRCA2):c.1000C>T (p.His334Tyr)

dbSNP: rs1593891725

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001181496	SCV001346649	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-18	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 334 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.
Invitae	RCV001876028	SCV002178007	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-29	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 921842). 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 histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 334 of the BRCA2 protein (p.His334Tyr).
Ambry Genetics	RCV001181496	SCV002636390	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-28	criteria provided, single submitter	clinical testing	The p.H334Y variant (also known as c.1000C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1000. The histidine at codon 334 is replaced by tyrosine, an amino acid with similar properties. This alteration was not observed in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001181496	SCV003849766	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).