ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.1136G>T (p.Arg379Leu)

dbSNP: rs863224682
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV001527092 SCV001737931 likely benign Li-Fraumeni syndrome 1 2021-04-02 reviewed by expert panel curation This variant is absent in the gnomAD cohort (PM2_Supporting; This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor(s)). Transactivation assays show a 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). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). In summary, TP53 c.1136G>T (p.Arg379Leu) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BS2_Supporting, BS3_Supporting, BP4.
Invitae RCV000199273 SCV000254625 uncertain significance Li-Fraumeni syndrome 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 379 of the TP53 protein (p.Arg379Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 216463). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). 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 RCV000219990 SCV000275804 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-28 criteria provided, single submitter clinical testing The p.R379L variant (also known as c.1136G>T), located in coding exon 10 of the TP53 gene, results from a G to T substitution at nucleotide position 1136. The arginine at codon 379 is replaced by leucine, an amino acid with dissimilar properties. This variant is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc Natl Acad Sci U S A, 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat Genet, 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590314 SCV000697426 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing Variant summary: The TP53 c.1136G>T (p.Arg379Leu) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant. This variant is absent in 121384 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health RCV000219990 SCV001359320 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-02 criteria provided, single submitter clinical testing This missense variant replaces arginine with leucine at codon 379 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). In functional studies, the mutant protein has shown ~70% of wild-type activity in yeast transactivation assays (IARC database and PMID: 12826609) and normal function in human cell growth suppression assays (PMID: 30224644). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx RCV000590314 SCV001792406 uncertain significance not provided 2020-10-13 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate partially functional transactivation (Kato 2003); This variant is associated with the following publications: (PMID: 12826609)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590314 SCV002046219 uncertain significance not provided 2020-09-16 criteria provided, single submitter clinical testing

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