ClinVar Miner

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

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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) 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 2019-12-15 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 Other data supporting benign classification;In silico models in agreement (benign)
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 RCV000427206 SCV000512308 likely benign not specified 2017-10-09 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 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 RCV000588512 SCV000885070 likely benign not provided 2017-10-15 criteria provided, single submitter clinical testing The BRCA1 c.4327C>G; p.Arg1443Gly variant is published in the medical literature with a low probability of pathogenicity (Carvalho 2007, Iversen 2011, Lindor 2012). The variant is listed as benign or likely benign by several clinical laboratories in the ClinVar database (Variation ID: 17676). The variant is listed in the dbSNP variant database (rs41293455) with a low allele frequency in the Genome Aggregation Database (9/277118 alleles). The arginine at this position is weakly conserved across species and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is tolerated. Additionally, this variant is reported to behave as wild type in at least one functional assay (Bouwman 2013). Considering available information, this variant is classified as likely benign. References: Bouwman P et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov. 2013 Oct;3(10):1142-55. Carvalho MA et al. Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis.Cancer Res. 2007 Feb 15;67(4):1494-501. Iversen ES Jr et al. A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1. Cancer Epidemiol Biomarkers Prev. 2011 Jun;20(6):1078-88. Lindor NM et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat. 2012 Jan;33(1):8-21.
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 2018-08-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000427206 SCV001360565 likely benign not specified 2019-11-29 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 (gnomAD). 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 pathogenic variants have been reported (BRCA1 c.269_281del, p.Ile90SerfsX25, UMD; BRCA1 c.3G>T, p.Met1Ile, BIC), providing supporting evidence for a benign role. Multiple 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). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (7x benign/likely benign, 1x VUS). Based on the evidence outlined above, the variant was classified as likely benign.
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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