Submissions for variant NM_000059.4(BRCA2):c.9632C>A (p.Thr3211Lys)

dbSNP: rs730881583

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160193	SCV000210540	uncertain significance	not provided	2018-11-30	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9632C>A at the cDNA level, p.Thr3211Lys (T3211K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 9860C>A. This variant has been observed in at least one individual with a history of breast cancer (Spearman 2008). BRCA2 Thr3211Lys was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. While protein-based in silico analysis supports that this variant does not alter protein structure/function, splicing models predict the creation of a novel splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 Thr3211Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000163095	SCV000213602	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-23	criteria provided, single submitter	clinical testing	The p.T3211K variant (also known as c.9632C>A), located in coding exon 25 of the BRCA2 gene, results from a C to A substitution at nucleotide position 9632. The threonine at codon 3211 is replaced by lysine, an amino acid with some similar properties. 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	RCV000472534	SCV000549709	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 3211 of the BRCA2 protein (p.Thr3211Lys). This variant is not present in population databases (gnomAD no frequency). 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: 182275). 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	RCV000163095	SCV000903228	likely benign	Hereditary cancer-predisposing syndrome	2015-09-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462082	SCV004213649	uncertain significance	Familial cancer of breast	2023-08-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998460	SCV004846208	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700493	SCV005205158	uncertain significance	not specified	2024-06-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9632C>A (p.Thr3211Lys) 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 1.2e-06 in 1613970 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9632C>A has been reported in the literature in at least two individuals with a history of cancer (e.g, Spearman_2008, Zhang_2015). However, these report(s) do not provide unequivocal conclusions about association of the variant with BRCA2-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18824701, 26580448). ClinVar contains an entry for this variant (Variation ID: 182275). Based on the evidence outlined above, the variant was classified as uncertain significance.