ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs587778718
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Total submissions: 12
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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 2022-06-21 reviewed by expert panel curation Transactivation assays show 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.572C>G (p.Pro191Arg) 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: BS3
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)
Invitae RCV000205751 SCV000261596 uncertain significance Li-Fraumeni syndrome 2022-07-12 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). ClinVar contains an entry for this variant (Variation ID: 127816). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function. 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 2023-08-15 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 2022-09-17 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.000062 (3/48326 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with papillary thyroid cancer (PMID: 27297285 (2016)), mantle cell lymphoma (PMID: 28819011 (2017)), and medulloblastoma (PMID: 33051313 (2021)). However, it did not appear to cosegregate with disease in two families (PMIDs: 27297285 (2016) and 33051313 (2021)). Functional studies indicate that this variant retains significant transactivation activity (PMID: 33051313 (2021), 29979965 (2018), 12826609 (2003) and NCI TP53 Database (https://tp53.isb-cgc.org/)), and does not have a dominant-negative effect (PMID: 30224644 (2018)). 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

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