Submissions for variant NM_000059.4(BRCA2):c.6061C>T (p.His2021Tyr)

dbSNP: rs1566233813

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706136	SCV000835168	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-06-23	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with tyrosine at codon 2021 of the BRCA2 protein (p.His2021Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tyrosine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics	RCV002352214	SCV002657690	uncertain significance	Hereditary cancer-predisposing syndrome	2015-12-31	criteria provided, single submitter	clinical testing	The p.H2021Y variant (also known as c.6061C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 6061. The histidine at codon 2021 is replaced by tyrosine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0004% (greater than 225000 alleles tested) in our clinical cohort. 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 p.H2021Y remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002352214	SCV003850890	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).