Submissions for variant NM_000059.4(BRCA2):c.10249T>C (p.Tyr3417His)

gnomAD frequency: 0.00001  dbSNP: rs535952730

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474923	SCV000549673	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 3417 of the BRCA2 protein (p.Tyr3417His). This variant is present in population databases (rs535952730, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 409517). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV000574730	SCV000668864	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-21	criteria provided, single submitter	clinical testing	The p.Y3417H variant (also known as c.10249T>C), located in coding exon 26 of the BRCA2 gene, results from a T to C substitution at nucleotide position 10249. The tyrosine at codon 3417 is replaced by histidine, an amino acid with similar properties. 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.
GeneDx	RCV000615202	SCV000724263	likely benign	not specified	2017-10-30	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health	RCV000574730	SCV000906836	likely benign	Hereditary cancer-predisposing syndrome	2017-05-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284407	SCV001470192	uncertain significance	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000615202	SCV004099928	uncertain significance	not specified	2023-09-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.10249T>C (p.Tyr3417His) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10249T>C has been reported in the literature in at-least one individual undergoing diagnostic genetic testing, without strong evidence for causality (example, Wai_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32123317). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=3; Likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.