Submissions for variant NM_000059.4(BRCA2):c.205C>A (p.Pro69Thr)

dbSNP: rs876658614

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221923	SCV000274104	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-04	criteria provided, single submitter	clinical testing	The p.P69T variant (also known as c.205C>A), located in coding exon 2 of the BRCA2 gene, results from a C to A substitution at nucleotide position 205. The proline at codon 69 is replaced by threonine, an amino acid with highly similar properties. This alteration was identified in a breast/ovarian cancer cohort from Peru (Ferreyra Y et al. Front Oncol, 2023 Aug;13:1227864). 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.
GeneDx	RCV000759586	SCV000293552	uncertain significance	not provided	2022-12-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 433C>A; This variant is associated with the following publications: (PMID: 24356096, 31853058, 29884841, 32377563, 31911673)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689076	SCV000816714	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 69 of the BRCA2 protein (p.Pro69Thr). 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: 230525). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759586	SCV000888999	uncertain significance	not provided	2020-02-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000221923	SCV000904866	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 69 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 ovarian cancer (PMID: 37664050) and in an individual affected with BRCA2-associated cancer and/or relevant family history (Color internal data). 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	RCV001797679	SCV002041748	uncertain significance	not specified	2024-09-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.205C>A (p.Pro69Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251386 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.205C>A has been reported in the literature as a VUS in individuals who met the clinical criteria for BRCA1/2 testing (Herzog_2021). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been observed (BRCA1 exon 16 deletion, internal data), providing supporting evidence for a benign role. 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: 34413315). ClinVar contains an entry for this variant (Variation ID: 230525). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003462442	SCV004213645	uncertain significance	Familial cancer of breast	2023-08-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997843	SCV004846743	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 69 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 ovarian cancer (PMID: 37664050) and in an individual affected with BRCA2-associated cancer and/or relevant family history (Color internal data). 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.