Submissions for variant NM_000059.4(BRCA2):c.8324T>C (p.Met2775Thr)

dbSNP: rs80359073

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045473	SCV000073486	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130178	SCV000185015	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	The p.M2775T variant (also known as c.8324T>C), located in coding exon 17 of the BRCA2 gene, results from a T to C substitution at nucleotide position 8324. The methionine at codon 2775 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000213690	SCV000279340	likely benign	not provided	2019-07-05	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10923033, 19043619)
Color Diagnostics, LLC DBA Color Health	RCV000130178	SCV000683954	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 2775 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with prostate cancer (PMID: 31214711). This variant has been identified in 3/31408 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.
Counsyl	RCV000113902	SCV000785492	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-08-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213690	SCV001133930	uncertain significance	not provided	2020-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222369	SCV002500150	uncertain significance	not specified	2022-03-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8324T>C (p.Met2775Thr) results in a non-conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247808 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8324T>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely benign n=1, VUS n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004537209	SCV004116462	uncertain significance	BRCA2-related disorder	2023-06-20	criteria provided, single submitter	clinical testing	The BRCA2 c.8324T>C variant is predicted to result in the amino acid substitution p.Met2775Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.034% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32937663-T-C) and has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52546/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000113902	SCV004845638	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 2775 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with prostate cancer (PMID: 31214711). This variant has been identified in 3/31408 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.
Baylor Genetics	RCV004566850	SCV005059205	uncertain significance	Familial cancer of breast	2023-11-03	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113902	SCV000147319	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-06-20	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000113902	SCV004228447	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP4(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)