ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3657G>C (p.Glu1219Asp) (rs80356876)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203654 SCV000076288 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 1219 of the BRCA1 protein (p.Glu1219Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs80356876, ExAC 0.004%). This variant has been reported in individuals affected with breast cancer and renal cancer (PMID: 8776600, 26689913). ClinVar contains an entry for this variant (Variation ID: 37537). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000131238 SCV000186193 likely benign Hereditary cancer-predisposing syndrome 2017-07-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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
Integrated Genetics/Laboratory Corporation of America RCV000589430 SCV000699054 uncertain significance not provided 2017-07-27 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3657G>C (p.Glu1219Asp) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). One functional study showed that BRCA1 p.E1219D was comparable to the wild-type BRCA1 in homology-directed repair assay (Lu_BRCA_Nature Comms_2015). Though Gly at 1219 is known to be conserved in mammals, it is not widely conserved in non-mammals, as Asp was found at codon 1219 in chicken and frog (Pavlicek_2004, Abkevich_2004 and Szabo_1996). This variant was reported in one suspected HBOC patient (Durocher_HMG_1996). This variant was found in 3/121386 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). One internal LCA sample with this variant also carries a deleterious variant in BRCA2 (c.4471_4474delCTGA), suggesting that the variant of concern is possibly benign. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/uncertain significance. Taken together, this variant is classified as VUS-possibly benign.
Color 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 Neoplasm of the breast 2014-06-01 no assertion criteria provided research

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