Submissions for variant NM_000059.4(BRCA2):c.340C>T (p.His114Tyr)

dbSNP: rs587778129

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758883	SCV000887789	uncertain significance	not provided	2017-11-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001020230	SCV001181683	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	The p.H114Y variant (also known as c.340C>T), located in coding exon 3 of the BRCA2 gene, results from a C to T substitution at nucleotide position 340. The histidine at codon 114 is replaced by tyrosine, an amino acid with similar properties. One study detected this alteration in 1/64 Chilean high-risk breast and/or ovarian cancer families (Jara L et al. Cancer Genet. Cytogenet., 2006 Apr;166:36-45).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	RCV001041097	SCV001204693	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-10	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 114 of the BRCA2 protein (p.His114Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 16616110). ClinVar contains an entry for this variant (Variation ID: 133743). 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.
Color Diagnostics, LLC DBA Color Health	RCV001020230	SCV001339710	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-30	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 114 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 16616110, 20859677). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120384	SCV002014917	uncertain significance	not specified	2021-10-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.340C>T (p.His114Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 252376 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.340C>T has been reported in at least one individual affected with Hereditary Breast And Ovarian Cancer without strong evidence for causality (Jara_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 . All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000758883	SCV003830154	uncertain significance	not provided	2023-07-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460847	SCV004213663	uncertain significance	Familial cancer of breast	2023-08-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997343	SCV004846764	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 114 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 16616110, 20859677). 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.
GeneDx	RCV000758883	SCV005079919	uncertain significance	not provided	2023-12-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 568C>T; This variant is associated with the following publications: (PMID: 24728327, 16616110, 20859677, 29884841, 32377563, 35402282)
ITMI	RCV000120384	SCV000084536	not provided	not specified	2013-09-19	no assertion provided	reference population