Submissions for variant NM_000059.4(BRCA2):c.4399C>T (p.His1467Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1064793495

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484223	SCV000566253	uncertain significance	not provided	2015-04-14	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4399C>T at the cDNA level, p.His1467Tyr (H1467Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). Using alternate nomenclature, this variant would be defined as BRCA2 4627C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 His1467Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 His1467Tyr occurs at a position that is not conserved across species and is located in the region of interaction with POLH and required for stimulation of POLH DNA polymerization activity (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 His1467Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484223	SCV001133794	uncertain significance	not provided	2019-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001022418	SCV001184151	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	The p.H1467Y variant (also known as c.4399C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 4399. The histidine at codon 1467 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported with a carrier frequency of 0.00014 in 7051 unselected breast cancer patients and was not reported in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration has also been reported with a carrier frequency of 0.00013 in 7636 unselected prostate cancer patients and 0.00024 in 12366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001050664	SCV001214783	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-29	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1467 of the BRCA2 protein (p.His1467Tyr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 418878). 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 with a negative predictive value of 95%. 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	RCV001022418	SCV003850480	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).