Submissions for variant NM_000059.4(BRCA2):c.575T>C (p.Met192Thr)

dbSNP: rs80358805

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000074544	SCV000072759	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000417374	SCV000108629	likely benign	not specified	2016-10-05	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.
Ambry Genetics	RCV000219992	SCV000275612	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-20	criteria provided, single submitter	clinical testing	The p.M192T variant (also known as c.575T>C), located in coding exon 6 of the BRCA2 gene, results from a T to C substitution at nucleotide position 575. The methionine at codon 192 is replaced by threonine, an amino acid with similar properties. This alteration has been reported as a variant of uncertain significance in 1 of 31 cases of familial pancreatic cancer, where at least two of the affected persons were first-degree relatives (Murphy K et al, Cancer Res. 2002 Jul; 62(13):3789-9). It has also been reported in 1 of 333 women with a breast cancer diagnosis at or less than 45 years of age (Haffty BG et al. Ann. Oncol., 2009 Oct;20:1653-9). This alteration has been reported with a carrier frequency of 0.0000 in 53 unselected male breast cancer patients and 0.0001 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is highly 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.
Counsyl	RCV000083120	SCV000487956	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985251	SCV000600664	uncertain significance	not provided	2019-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219992	SCV000683731	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-14	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 192 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 observed in an individual affected with breast cancer (PMID: 19491284) and an unaffected control from a breast cancer case-control study (PMID: 30287823). This variant also has been observed in an individual affected with familial pancreatic cancer (PMID: 12097290). 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	RCV000417374	SCV000916829	uncertain significance	not specified	2024-10-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.575T>C (p.Met192Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In a splicing minigene reporter assay, the variant was shown not to affect splicing (Di Giacomo_2013). The variant was absent in 251414 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.575T>C has been reported in the literature in individuals affected with pancreatic cancer or early onset breast cancer (Murphy_2002, Haffty_2009). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.2722G>T, p.Glu908*; BRCA2 c.7069_7070del, p.Leu2357Valfs*2), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 37415649, 18403564, 23983145, 19064968, 19491284, 21702907, 20167696, 18657973, 30287823, 12097290, 26761715). ClinVar contains an entry for this variant (Variation ID: 51930). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000417374	SCV002550257	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460595	SCV004213629	uncertain significance	Familial cancer of breast	2024-03-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000083120	SCV004846791	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 192 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 observed in an individual affected with breast cancer (PMID: 19491284) and an unaffected control from a breast cancer case-control study (PMID: 30287823). This variant also has been observed in an individual affected with familial pancreatic cancer (PMID: 12097290). 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.
Sharing Clinical Reports Project (SCRP)	RCV000083120	SCV000115194	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083120	SCV000147197	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000985251	SCV001954433	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000985251	SCV001969291	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000985251	SCV001978613	uncertain significance	not provided		no assertion criteria provided	clinical testing