ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3657G>C (p.Glu1219Asp) (rs80356876)

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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) RCV000031118 SCV001161586 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 = 0.000503
Invitae RCV000203654 SCV000076288 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131238 SCV000186193 likely benign Hereditary cancer-predisposing syndrome 2018-11-06 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
GeneDx RCV000589430 SCV000209954 uncertain significance not provided 2018-07-24 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3657G>C at the cDNA level, p.Glu1219Asp (E1219D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). Using alternate nomenclature, this variant would be defined as BRCA1 3776G>C. This variant has been observed in an individual with a personal and family history of breast cancer (Durocher 1996). BRCA1 Glu1219Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Glu1219Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000589430 SCV000224996 uncertain significance not provided 2014-09-09 criteria provided, single submitter clinical testing
Counsyl RCV000031118 SCV000487784 uncertain significance Breast-ovarian cancer, familial 1 2015-12-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048275 SCV000600338 uncertain significance not specified 2017-07-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048275 SCV000699054 benign not specified 2020-07-06 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3657G>C (p.Glu1219Asp) results in a 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 1.6e-05 in 251288 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3657G>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Durocher_1996). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA2 c.4471_4474delCTGA, p.Leu1491fsX12; Internal testing), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function through utilization of a homology-directed DNA repair assay demonstrated the variant to perform equivalently to the wild-type (Lu_2015). Seven ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=4) and as uncertain significance (n=3). An expert panel (ENIGMA) (evaluation after 2014) cites the variant as benign based on utilization of a multifactorial likelihood model encompassing likelihood ratios (LRs) for pathogenicity estimated from clinical data of co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology and bioinformatic predictions (Parsons_2019). Based on the evidence outlined above, the variant was classified as benign.
Color Health, Inc RCV000131238 SCV000903171 likely benign Hereditary cancer-predisposing syndrome 2017-11-10 criteria provided, single submitter clinical testing
Mendelics RCV000031118 SCV001140549 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031118 SCV000053716 likely benign Breast-ovarian cancer, familial 1 2008-06-12 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031118 SCV000144827 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148382 SCV000190080 likely benign Breast neoplasm 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000031118 SCV001550879 likely benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Glu1219Asp variant was identified in 2 of 8356 proband chromosomes (frequency: 0.0002) from individuals or families with breast, ovarian or renal cancer and was not identified in 128 control chromosomes from healthy individuals (Durocher 1996, Lu 2015). The variant was also identified in dbSNP (ID: rs80356876) as "With Likely benign, Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics, Color and SCRP; as uncertain significance Invitae, Counsyl and five other submitters), LOVD 3.0 (4x as unclassified variant), and UMD-LSDB (2x as unclassified variant). Integrated Genetics/Laboratory Corporation of America reported identifying the variant with a co-occurring, deleterious variant in BRCA2 (c.4471_4474delCTGA), increasing the likelihood that the p.Glu1219Asp variant does not have clinical significance. The variant was identified in control databases in 5 of 246040 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 5 of 111534 chromosomes (freq: 0.00005), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Glu1219 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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