ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6290C>T (p.Thr2097Met) (rs80358866)

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Total submissions: 14
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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 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
Invitae RCV000588166 SCV000072902 likely benign not provided 2019-02-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131379 SCV000186355 likely benign Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,In silico models in agreement (benign)
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 RCV000131379 SCV000683767 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 2 2018-02-27 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000588166 SCV000805737 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing
Mendelics RCV000044889 SCV000838836 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588166 SCV000889098 likely benign not provided 2019-07-09 criteria provided, single submitter clinical testing
Mendelics RCV000031613 SCV001139142 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031613 SCV000054220 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031613 SCV000146810 uncertain significance Breast-ovarian cancer, familial 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

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