ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.431A>T (p.Gln144Leu)

dbSNP: rs786203071
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000991148 SCV001142559 uncertain significance Li-Fraumeni syndrome 2024-08-05 reviewed by expert panel curation The NM_000546.6: c.431A>T variant in TP53 is a missense variant predicted to cause substitution of Glutamine by Leucine at amino acid 144 (p.Gln144Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity, indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, the computational splicing predictor SpliceAI gives a score of 0.00, predicting that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met). Another missense variant with equal or lesser predicted impact c.431A>C (p.Gln144Pro) (ClinVar Variation ID: 186594), in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5_Supporting). This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). Due to conflicting evidence, this variant is classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3_Supporting, PM2_Supporting, PM5_Supporting, PM1_Supporting. (Bayesian Points: 2; VCEP specifications version 2.0; 7/24/2024)

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.