ClinVar Miner

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

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Total submissions: 12
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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 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV001719791 SCV000210556 likely benign not provided 2020-12-16 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26689913, 18284688, 24916970, 15876480, 21990134, 17924331, 24323938, 23315985, 27153395, 26332594, 29580235)
Ambry Genetics RCV000162998 SCV000213486 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000173635 SCV000694510 benign not specified 2020-08-24 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 0.00018 in 143210 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD v3 database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. 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. At least one 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. Six ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as benign (3x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as benign.
Color Health, Inc RCV000162998 SCV000902815 benign Hereditary cancer-predisposing syndrome 2016-08-31 criteria provided, single submitter clinical testing
Mendelics RCV000083085 SCV001138989 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642584 SCV001854663 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
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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