Submissions for variant NM_000059.4(BRCA2):c.6290C>T (p.Thr2097Met)

gnomAD frequency: 0.00004  dbSNP: rs80358866

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031613	SCV001161522	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000217
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044889	SCV000072902	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131379	SCV000186355	likely benign	Hereditary cancer-predisposing syndrome	2019-01-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV000423925	SCV000512379	likely benign	not specified	2017-12-06	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.
Color Diagnostics, LLC DBA Color Health	RCV000131379	SCV000683767	likely benign	Hereditary cancer-predisposing syndrome	2015-11-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000423925	SCV000694957	uncertain significance	not specified	2019-07-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6290C>T (p.Thr2097Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.5e-05 in 292890 control chromosomes (gnomAD and publication data). This frequency is not higher than the estimated maximum for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (7.5e-05 vs 0.00075), allowing no conclusion about variant significance. The variant, c.6290C>T, has been reported in the literature in individuals affected with breast- and/or ovarian cancer without strong evidence for causality (Diez_2003, Gonzalez_2011, Vail_2015, Alvarez_2017, Zuntini_2018, Momozawa_2018), and was also found in unaffected controls (Momozawa_2018, and in the FLOSSIES database). In one report, the variant did not segregate with disease in a family, suggesting it may not be the cause of cancer in the family (Zuntini_2018). Thus, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a pathogenic BRCA2 variant has been reported (c.7414_7415delAA, p.Lys2472Valfs; in the BIC database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, without evidence for independent evaluation, and classified the variant as VUS (3x) or likely benign (6x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000031613	SCV000786119	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588166	SCV000889098	likely benign	not provided	2023-08-04	criteria provided, single submitter	clinical testing
Mendelics	RCV000031613	SCV001139142	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000588166	SCV001714433	uncertain significance	not provided	2019-04-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588166	SCV002050278	likely benign	not provided	2022-06-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131379	SCV002536219	likely benign	Hereditary cancer-predisposing syndrome	2020-12-16	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000423925	SCV002761171	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031613	SCV004846731	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-11	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031613	SCV000054220	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031613	SCV000146810	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000131379	SCV000805245	likely benign	Hereditary cancer-predisposing syndrome	2018-04-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732571	SCV000805737	likely benign	BRCA2-related disorder	2024-08-22	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Medical and Surgical Sciences, University of Bologna	RCV000031613	SCV004228425	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Strong)+BP1(Strong)+BP5(Strong) 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)