ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4327C>G (p.Arg1443Gly) (rs41293455)

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Total submissions: 15
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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) RCV000019245 SCV001161592 benign Breast-ovarian cancer, familial 1 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 = 2.23E-06
Invitae RCV000048522 SCV000076535 benign Hereditary breast and ovarian cancer syndrome 2020-11-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129043 SCV000172955 likely benign Hereditary cancer-predisposing syndrome 2019-01-25 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Michigan Medical Genetics Laboratories,University of Michigan RCV000019245 SCV000195928 uncertain significance Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
Counsyl RCV000019245 SCV000488475 benign Breast-ovarian cancer, familial 1 2016-04-20 criteria provided, single submitter clinical testing
GeneDx RCV000588512 SCV000512308 likely benign not provided 2019-05-08 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18992264, 25556971, 28781887, 21990134, 7894491, 21447777, 23867111, 25525159, 17308087, 19369211, 26295337, 25652403, 28569743, 30765603, 33087888)
Color Health, Inc RCV000129043 SCV000683171 likely benign Hereditary cancer-predisposing syndrome 2015-01-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282125 SCV000885070 likely benign none provided 2020-04-18 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588512 SCV000892186 likely benign not provided 2018-07-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588512 SCV001133581 likely benign not provided 2020-02-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000427206 SCV001360565 benign not specified 2020-12-28 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4327C>G (p.Arg1443Gly) 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 3.2e-05 in 251364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.4327C>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (e.g. Ahmed_2012, Alsop_2012, Castilla_1994, Haffty_2009, Judkins_2005, Trujillano_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in the BIC and UMD databases respectively (BRCA1 c.3G>T, p.Met1Ile; BRCA1 c.269_281del, p.Ile90SerfsX25), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Bouwman_2013, Carvalho_2007, Sy_2009, Woods_2016, Fernandes_2019). Nine clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=3, likely benign, n=6, VUS, n=1). Based on the evidence outlined above, to reflect the emerging consensus towards a benign outcome, the variant was classified as benign.
Research and Development, ARUP Laboratories RCV001659714 SCV001878367 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
OMIM RCV000019245 SCV000039533 pathogenic Breast-ovarian cancer, familial 1 1994-12-01 no assertion criteria provided literature only
Breast Cancer Information Core (BIC) (BRCA1) RCV000019245 SCV000145056 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000048522 SCV000503551 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-08-01 no assertion criteria provided research Found in a 37 year old female patient having exome sequencing for an unrelated indication. No known history of breast cancer. Family history of a mother with breast ancer diagnosed at 50, a maternal grandmother who died of breast cancer at age 58 and a paternal grandmother diagnosed with breast and ovarian cancer.

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