Submissions for variant NM_000546.6(TP53):c.11C>T (p.Pro4Leu)

dbSNP: rs878854064

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000229754	SCV001949907	likely benign	Li-Fraumeni syndrome	2025-01-16	reviewed by expert panel	curation	The NM_000546.6: c.11C>T variant in TP53 is a missense variant predicted to cause substitution of proline by leucine at amino acid 4 (p.Pro4Leu). This variant has an allele frequency of 6.196e-7 (1/1613946 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.062909; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS3, BP4. (Bayesian Points: -4; VCEP specifications version 2.0; 1/16/2025)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229754	SCV000285174	uncertain significance	Li-Fraumeni syndrome	2024-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the TP53 protein (p.Pro4Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 237941). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. 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	RCV000571530	SCV000672384	likely benign	Hereditary cancer-predisposing syndrome	2021-01-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000662489	SCV000784994	uncertain significance	Li-Fraumeni syndrome 1	2017-03-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759369	SCV000888659	uncertain significance	not provided	2019-01-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780782	SCV000918324	uncertain significance	not specified	2023-10-23	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.11C>T (p.Pro4Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250676 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.11C>T has been reported in the literature in an individual affected with breast cancer, however it was identified as a somatic variant (Ellis_2012; COSMIC). This report does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The IARC TP53 database reports this variant to be functional based on transcriptional activity in yeast (Kato 2003). In addition, a loss-of-function saturation mutagenesis screen indicated that this missense does not substantially affect TP53 function (Giacomelli_2018). The following publications have been ascertained in the context of this evaluation (PMID: 22722193, 12826609, 30224644). Seven other submitters, including an expert panel, have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=5) or likely benign (n=2; including the expert panel). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV000571530	SCV001349332	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 4 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study in yeast has shown that this variant does not impair transcriptional transactivation activity of TP53 (IARC database; PMID: 12826609). 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.
Myriad Genetics, Inc.	RCV000662489	SCV004017881	uncertain significance	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV000229754	SCV004823874	uncertain significance	Li-Fraumeni syndrome	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 4 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant was neutral in yeast transcriptional transactivation and human cell growth suppression assays (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders 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.