ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1123C>T (p.Pro375Ser) (rs80358408)

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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) RCV000083085 SCV000244417 benign Breast-ovarian cancer, familial 2 2015-08-10 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 = 0.0000648
Invitae RCV000195325 SCV000071753 benign Hereditary breast and ovarian cancer syndrome 2018-01-12 criteria provided, single submitter clinical testing
GeneDx RCV000173635 SCV000210556 likely benign not specified 2017-11-06 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.
Ambry Genetics RCV000162998 SCV000213486 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
Counsyl RCV000083085 SCV000220527 likely benign Breast-ovarian cancer, familial 2 2014-07-21 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000173635 SCV000224765 likely benign not specified 2015-03-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000173635 SCV000694510 likely benign not specified 2019-05-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1123C>T (p.Pro375Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250158 control chromosomes (gnomAD, exome dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in the literature in individuals affected with breast- and ovarian cancer (Lee_2008, Salazar_2006, Peixoto_2014, Maistro_2016, Maxwell_2016). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with another pathogenic variant has been reported (BRCA1 c.211A>G (p.Arg71Gly) in the NHGRI BIC database), providing supporting evidence for a benign role. Multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton 2007 and Lindor 2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other submitters, including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=2) / benign (n=2 to include the expert panel). Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV000162998 SCV000902815 benign Hereditary cancer-predisposing syndrome 2016-08-31 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083085 SCV000115159 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083085 SCV000145815 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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