ClinVar Genomic variation as it relates to human health

This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). 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). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). In summary, TP53 c.344A>G (p.His115Arg) 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, BS3, BP4. In this case, PM2_Supporting should not be applied as there is sufficient evidence codes for variant to meet Likely Benign classification.

Variant summary: The variant, TP53 c.344A>G (p.His115Arg) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of 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 245988 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.344A>G in individuals affected with Li-Fraumeni Syndrome or related tumor phenotypes has been reported. Publications reported experimental evidence evaluating an impact on protein function, where one study demonstrated that the variant, p.H115R, does not affect the transactivation activity on eight different promoter elements (including p21) (data taken from the IARC Database, reference: Kato 2003), while another study demonstrated that the variant protein has a decreased oligonucleotide binding activity in an EMSA assay (where the probe contained the p53 response element from the p21 promoter) (Zupnick 2006). These data does not allow unequivocal conclusions about the variant effect. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16687402, 27527004, 11313981, 31395738, 29979965)

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 115 of the TP53 protein (p.His115Arg). 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: 182925). 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, 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.

This missense variant replaces histidine with arginine at codon 115 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to exhibit normal transactivation activity in a yeast transactivation assay (PMID 12826609 and IARC database) and to be functional in human cell growth assays (PMID: 29979965, 30224644). The mutant protein has shown a partially reduced binding affinity for the p53 response element from the p21 promoter (PMID: 16687402). 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.

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.