ClinVar Genomic variation as it relates to human health

The TP53 c.665C>T; p.Pro222Leu variant (rs146340390) is reported in the literature in several individuals suspected of having Li-Fraumeni syndrome (Ruijs 2010) or Lynch syndrome (Yurgelun 2015), though it was also found in an individual not selected for a history of cancer (de Andrade 2017). This variant is reported in ClinVar (Variation ID: 161397) and is found on six chromosomes in the Genome Aggregation Database. The proline at codon 222 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. In functional assays, the p.Pro222Leu variant exhibits comparable transcriptional activation activity to wildtype protein (Grochova 2008, Slovackova 2010). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: de Andrade KC et al. Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history. Hum Mutat. 2017 Dec;38(12):1723-1730. Grochova D et al. Analysis of transactivation capability and conformation of p53 temperature-dependent mutants and their reactivation by amifostine in yeast. Oncogene. 2008 Feb 21;27(9):1243-52. Ruijs MW et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet. 2010 Jun;47(6):421-8. Slovackova J et al. Transactivation by temperature-dependent p53 mutants in yeast and human cells. Cell Cycle. 2010 Jun 1;9(11):2141-8. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21232794, 28745575, 20504876, 25742471, 29979965, 30582853, 25637381, 20522432, 20505364, 17724467, 25980754, 19336573, 26917275, 15781620, 14559903, 12909720, 28364582, 28492532, 12826609, 30352134, 28230820, 17311302, 30224644, 23897043, 28861920, 30840781, 31159747, 30588330, 23484829, 31439692)

Variant summary: TP53 c.665C>T (p.Pro222Leu) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251328 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.665C>T has been reported in the literature in individuals affected with suspected Li-Fraumeni Syndrome, suspected Lynch syndrome, and leukemia (Yurgelun_2015, Ruijs_2010, Qian_2018, Wang_2013). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The variant was reported as functional in several experimental studies (ie. Kato_2003, Doffe_2020). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five submitters classified the variants as VUS while three classified as likely benign/benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces proline with leucine at codon 222 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Yeast and mammalian cell studies reported this variant to be functional, with some temperature-sensitive effects observed in yeast (PMID: 12826609, 15781620, 17724467, 20505364, 23897043, 29979965, 30224644). This variant has been reported in an individual with childhood-onset rhabdomyosarcoma (PMID: 20522432) and in an individual affected with early-onset breast cancer meeting the Chompret criteria (PMID: 35323354). This variant has also been observed in an individual affected with Li-Fraumeni syndrome who has a pathogenic p.Arg267Trp variant in the same gene (PMID: 23484829), and an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 6/282714 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

This missense variant replaces proline with leucine at codon 222 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Yeast and mammalian cell studies reported this variant to be functional, with some temperature-sensitive effects observed in yeast (PMID: 12826609, 15781620, 17724467, 20505364, 23897043, 29979965, 30224644). This variant has been reported in an individual with childhood-onset rhabdomyosarcoma (PMID: 20522432) and in an individual affected with early-onset breast cancer meeting the Chompret criteria (PMID: 35323354). This variant has also been observed in an individual affected with Li-Fraumeni syndrome who has a pathogenic p.Arg267Trp variant in the same gene (PMID: 23484829), and an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 6/282714 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

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.

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.

The TP53 c.665C>T variant is predicted to result in the amino acid substitution p.Pro222Leu. This variant has been reported as a germline variant in a patient with Li-Fraumeni syndrome (Ruijs et al. 2010. PubMed ID: 20522432) and in two patients with chronic lymphocytic leukemia while being absent from controls (Bilous et al. 2016. PubMed ID: 28230820). However, pathogenicity was not clearly established. This variant has been observed in only 6 out of ~282,000 alleles in a large population database and has been reported in ClinVar with conflicting interpretations ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.