ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2155A>G (p.Lys719Glu) (rs80357147)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203646 SCV000075745 likely benign Hereditary breast and ovarian cancer syndrome 2018-01-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131665 SCV000186693 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000587133 SCV000210123 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2155A>G at the cDNA level, p.Lys719Glu (K719E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). Using alternate nomenclature, this variant would be defined as BRCA1 2274A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Lys719Glu was observed at an allele frequency of 0.07% (18/24020) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located within the DNA binding domain and a region that interacts with RAD50 and STAT1 (Zhong 1999, Ouchi 2000, Narod 2004). 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 Lys719Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000855631 SCV000698924 uncertain significance not specified 2019-07-10 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2155A>G (p.Lys719Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found in the gnomAD database at a frequency of 4.8e-05 in 251194 control chromosomes, entirely within the African or African-American subpopulation at a frequency of 0.00062. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.8e-05 vs 0.001), allowing no conclusion about variant significance. c.2155A>G has been reported in the literature in individuals affected with or with a family history of Breast and Ovarian Cancer as well as unaffected individuals (Judkins_2005, Pal_2015, Abe_2019). These publications report no evidence for or against pathogenicity, and therfore do not provide conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: Five laboratories have classified the variant as uncertain significance, while two have classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000203646 SCV000839273 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000131665 SCV000903737 likely benign Hereditary cancer-predisposing syndrome 2015-04-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111777 SCV000144312 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000587133 SCV000778761 uncertain significance not provided 2018-02-26 no assertion criteria provided clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761067 SCV000890982 uncertain significance Neuroblastoma 2016-07-22 no assertion criteria provided clinical testing

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