Submissions for variant NM_000059.4(BRCA2):c.6806T>C (p.Ile2269Thr)

gnomAD frequency: 0.00001  dbSNP: rs398122564

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000230132	SCV000283299	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2269 of the BRCA2 protein (p.Ile2269Thr). This variant is present in population databases (rs398122564, gnomAD 0.0009%). This missense change has been observed in individual(s) with personal or family history of hereditary breast and/or ovarian cancer (PMID: 31409081). ClinVar contains an entry for this variant (Variation ID: 91456). 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.
Ambry Genetics	RCV000568704	SCV000665093	likely benign	Hereditary cancer-predisposing syndrome	2017-12-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000076973	SCV000785063	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000568704	SCV000906537	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 2269 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 2 individuals affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000713). This variant has been identified in 1/250510 chromosomes 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	RCV001527034	SCV001737857	uncertain significance	not specified	2021-05-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6806T>C (p.Ile2269Thr) results in a non-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 250510 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6806T>C has been reported in the literature as a likely benign variant in at-least one study of Czech patients with breast cancer (example, Machakova_2019). This report does 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001555262	SCV001776647	uncertain significance	not provided	2022-12-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of BRCA2-related cancers (Machackova et al., 2019); Also known as 7034T>C; This variant is associated with the following publications: (PMID: 31409081, 29884841, 32377563)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000568704	SCV003847464	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).
Sharing Clinical Reports Project (SCRP)	RCV000076973	SCV000108770	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-10-26	no assertion criteria provided	clinical testing