ClinVar Miner

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

dbSNP: rs878854064
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000662489 SCV001949907 likely benign Li-Fraumeni syndrome 1 2021-08-04 reviewed by expert panel curation This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show [retained/supertransactivation] function 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; PMID: 12826609, 30224644). In summary, TP53 c.11C>T (p.Pro4Leu) 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, BP4, BS3.
Invitae RCV000229754 SCV000285174 uncertain significance Li-Fraumeni syndrome 2023-12-06 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). Advanced modeling performed at Invitae incorporating data from internal and/or published 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%. 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 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 2023-09-05 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.

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.