ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7534C>T (p.Leu2512Phe) (rs80358980)

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Total submissions: 10
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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) RCV000113773 SCV001161533 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 = 0.000428
Invitae RCV001085013 SCV000073252 benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130690 SCV000185577 likely benign Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing Structural Evidence;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
GeneDx RCV000212260 SCV000210428 likely benign not specified 2017-10-26 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.
Counsyl RCV000113773 SCV000220890 likely benign Breast-ovarian cancer, familial 2 2014-11-14 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212260 SCV000600754 uncertain significance not specified 2017-04-27 criteria provided, single submitter clinical testing
Color RCV000130690 SCV000683885 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212260 SCV000695076 uncertain significance not specified 2019-12-20 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7534C>T (p.Leu2512Phe) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 348928 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7534C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence of causality (e.g. Zuntini_2018, Shimelis_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant(s) have been reported (BRCA1 c.4760C>G, p.Ser1587X), providing supporting evidence for a benign role (UMD database). In addition, several computational and multifactorial models suggest this variant as neutral or likely benign (Whiley_2014, Karchin_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters cite the variant as benign/likely benign (n=2) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113773 SCV000147115 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113773 SCV000297553 uncertain significance Breast-ovarian cancer, familial 2 2006-10-17 no assertion criteria provided clinical testing

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