ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.319T>C (p.Tyr107His) (rs368771578)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000991146 SCV001142553 benign Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant has a minor allele frequency of 0.001122 (0.11%, 28/24,948 alleles) in the African subpopulation of the gnomAD cohort (BA1). The variant also has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). Finally, this variant has been observed in at least 7 60+ year old females without a cancer diagnosis (BS2_Supporting; FLOSSIES database - https://whi.color.com). In summary, TP53 c.319T>C; p.Tyr107His meets criteria to be classified as benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BA1, BP4, BS3_Supporting, BS2_Supporting.
Ambry Genetics RCV000128936 SCV000172807 likely benign Hereditary cancer-predisposing syndrome 2019-02-16 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Other strong data supporting benign classification
GeneDx RCV000235219 SCV000211739 likely benign not specified 2018-01-25 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.
Invitae RCV000991146 SCV000285186 likely benign Li-Fraumeni syndrome 2020-11-24 criteria provided, single submitter clinical testing
Counsyl RCV000411273 SCV000489333 uncertain significance Li-Fraumeni syndrome 1 2016-09-22 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000235219 SCV000597523 likely benign not specified 2018-04-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588191 SCV000602266 likely benign not provided 2018-09-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235219 SCV000697439 benign not specified 2020-07-30 criteria provided, single submitter clinical testing Variant summary: TP53 c.319T>C (p.Tyr107His) results in a conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Functional studies based on the overall transcriptional activity in yeast assays classified this variant as partially functional (Kato_2003). The variant allele was found at a frequency of 0.00012 in 282734 control chromosomes, predominantly at a frequency of 0.0011 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. In addition, this variant was observed in old females, older than age 70 years who have never had cancer (FLOSSIES database). This variant has been reported in cancer patients without strong evidence for causality. Eight ClinVar submitters, including one expert panel (ClinGen TP53 Variant Curation Expert Panel, benign), (evaluation after 2014) cite the variant as uncertain significance (1x), likely benign (6x) and benign (1x). Based on the evidence outlined above, the variant was classified as benign.
Color Health, Inc RCV000128936 SCV000910800 likely benign Hereditary cancer-predisposing syndrome 2020-05-20 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000991146 SCV001439183 benign Li-Fraumeni syndrome 2020-09-03 criteria provided, single submitter clinical testing

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