ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.332T>C (p.Leu111Pro)

dbSNP: rs1057519997
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000459042 SCV000545305 uncertain significance Li-Fraumeni syndrome 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 111 of the TP53 protein (p.Leu111Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TP53-related conditions (PMID: 32817165). ClinVar contains an entry for this variant (Variation ID: 376630). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 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.
GeneDx RCV000480700 SCV000565622 likely pathogenic not provided 2023-04-06 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: loss of growth suppression and non-functional transcriptional activation activity (Kato et al., 2003; Kotler et al., 2018; Giacomelli et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual meeting Chompret criteria (Ozdemir et al., 2020); This variant is associated with the following publications: (PMID: 8934544, 7585578, 29979965, 16596195, 16000567, 12826609, 30224644, 15510160, Ozdemir2020[CaseReport], 32817165)
Myriad Genetics, Inc. RCV004022227 SCV004932441 likely pathogenic Li-Fraumeni syndrome 1 2024-02-13 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Molecular Diagnostics Laboratory, Catalan Institute of Oncology RCV004791445 SCV005407744 likely pathogenic Hereditary cancer-predisposing syndrome 2023-05-22 criteria provided, single submitter clinical testing c.332T>C, located in exon 4 of the TP53 gene, is predicted to result in the substitution of Leucine by Proline at codon 111, p.(Leu111Pro). This variant is not present in population databases (not reported in gnomADv2.1.1) (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. Computational tools predict no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.46) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). It has been reported in 2 Chompret families, which awards 1 point to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID 32817165) (PS4_supporting). The variant was also identified in the following databases, CancerHotspots (7 somatic observations), ClinVar (2x as likely pathogenic, 1x as uncertain significance), LOVD (2x as likely pathogenic). Based on the currently available information, c.332T>C is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785496 SCV000924068 likely pathogenic Ovarian neoplasm 2018-12-01 no assertion criteria provided research

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