Submissions for variant NM_000546.6(TP53):c.572C>G (p.Pro191Arg)

gnomAD frequency: 0.00001  dbSNP: rs587778718

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000205751	SCV001429617	likely benign	Li-Fraumeni syndrome	2025-01-16	reviewed by expert panel	curation	The NM_000546.6: c.572C>G variant in TP53 is a missense variant predicted to cause substitution of proline by arginine at amino acid 191 (p.Pro191Arg). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00005 (3/59996 alleles) in the Admixed American population (PM2, BS1, and BA1 are not met). 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 = 0.0942; Align GVGD Class 35) 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: BS3, BP4. (Bayesian Points: -5; VCEP specifications version 2.2; 1/16/2025)
GeneDx	RCV000766937	SCV000149636	likely benign	not provided	2019-04-15	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15523690, 27297285, 30321517, 29979965, 24728327, 23713777, 28861920, 12826609, 30840781)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205751	SCV000261596	uncertain significance	Li-Fraumeni syndrome	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 191 of the TP53 protein (p.Pro191Arg). This variant is present in population databases (rs587778718, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 27297285, 33051313, 35534704). ClinVar contains an entry for this variant (Variation ID: 127816). 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%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644, 33051313). 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	RCV000219468	SCV000276419	likely benign	Hereditary cancer-predisposing syndrome	2020-11-02	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.
Color Diagnostics, LLC DBA Color Health	RCV000219468	SCV000686752	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 191 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 this variant to be functional in yeast transcriptional transactivation and human cell proliferation and growth suppression assays (PMID: 12826609, 29979965, 30224644, 33051313). This variant has been reported in individuals affected with cancers consistent with Li-Fraumeni in the literature, but the variant did not appear to segregate with disease (PMID: 27297285) and the variant has been observed in a healthy cohort (PMID: 24728327). In a large case-control study the variant was found in 0/60466 cases and 5/53456 controls (PMID: 33471991). This variant has been identified in 3/251476 chromosomes 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.
Counsyl	RCV000662561	SCV000785162	uncertain significance	Li-Fraumeni syndrome 1	2017-05-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000219468	SCV002530468	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000122174	SCV002760882	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662561	SCV004017864	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766937	SCV004221365	uncertain significance	not provided	2024-09-23	criteria provided, single submitter	clinical testing	The TP53 c.572C>G (p.Pro191Arg) variant has been reported in the published literature in individuals with papillary thyroid cancer (PMID: 27297285 (2016)), mantle cell lymphoma (PMID: 28819011 (2017)), medulloblastoma (PMID: 33051313 (2021)), and breast cancer (PMID: 35534704 (2022)), as well as in a reportedly healthy individual in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). Functional studies demonstrated that this variant was not damaging to protein function (PMID: 33051313 (2021), 30224644 (2018), 29979965 (2018), 12826609 (2003) and NCI TP53 Database (https://tp53.isb-cgc.org/)). The frequency of this variant in the general population, 0.000012 (3/251476 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000205751	SCV004823784	uncertain significance	Li-Fraumeni syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 191 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 this variant to be functional in yeast transcriptional transactivation and human cell proliferation and growth suppression assays (PMID: 12826609, 29979965, 30224644, 33051313). This variant has been reported in individuals affected with cancers consistent with Li-Fraumeni in the literature, but the variant did not appear to segregate with disease (PMID: 27297285) and the variant has been observed in a healthy cohort (PMID: 24728327). In a large case-control study the variant was found in 0/60466 cases and 5/53456 controls (PMID: 33471991). This variant has been identified in 3/251476 chromosomes 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.
ITMI	RCV000122174	SCV000086389	not provided	not specified	2013-09-19	no assertion provided	reference population