ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2155A>G (p.Lys719Glu) (rs80357147)

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Total submissions: 12
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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 2020-11-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131665 SCV000186693 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-23 criteria provided, single submitter clinical testing The p.K719E variant (also known as c.2155A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 2155. The lysine at codon 719 is replaced by glutamic acid, an amino acid with similar properties. This variant has been identified in a cohort of high-risk pancreatic cancer families (Abe T et al. J. Clin. Oncol., 2019 05;37:1070-1080). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000587133 SCV000210123 uncertain significance not provided 2021-03-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or pancreatic cancer (Pal 2015, Abe 2019); Also known as 2274A>G; This variant is associated with the following publications: (PMID: 16267036, 15385441, 28135145, 26287763, 30883245)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855631 SCV000698924 uncertain significance not specified 2021-05-22 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 at a frequency of 4.8e-05 in 251194 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.001), allowing no conclusion about variant significance. However, the variant was reported in 5/2559 African American women (i.e. with an allele frequency of about 0.001), who were older than age 70, and have never had cancer (in the FLOSSIES database), suggesting that the variant might be a benign polymorphism. c.2155A>G, has been reported in the literature in individuals affected with or without a family history of Breast and Ovarian Cancer (Judkins_2005, Pal_2015, Abe_2019). These reports do not provide unequivocal 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. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=7; likely benign, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics RCV000203646 SCV000839273 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761067 SCV000890982 uncertain significance Neuroblastoma 2016-07-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131665 SCV000903737 likely benign Hereditary cancer-predisposing syndrome 2015-04-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587133 SCV001133515 likely benign not provided 2018-11-23 criteria provided, single submitter clinical testing
Mendelics RCV000111777 SCV001140582 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285574 SCV001472034 uncertain significance none provided 2019-10-13 criteria provided, single submitter clinical testing The BRCA1 c.2155A>G; p.Lys719Glu variant (rs80357147), is reported in the literature in at least one individual affected with breast cancer, though it was not demonstrated to be disease-causing (Pal 2015). This variant is found in the African population with an overall allele frequency of 0.08% (20/24898 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 37452). The lysine at codon 719 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Lys719Glu variant is uncertain at this time. References: Pal T et al. A high frequency of BRCA mutations in young black women with breast cancer residing in Florida. Cancer. 2015 Dec 1;121(23):4173-80.
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 Laboratories, Mayo Clinic RCV000587133 SCV000778761 uncertain significance not provided 2018-02-26 no assertion criteria provided clinical testing

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