TP53 NM_000546.5:c.1136G>A, Arg379His

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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 missense variant replaces arginine with histidine at codon 379 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have reported the mutant protein to be functional in yeast transactivation assays (PMID: 12826609) and in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 26086041) as well as in individuals without cancer (PMID: 30287823, 32980694). This variant has been identified in 2/282792 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.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 379 of the TP53 protein (p.Arg379His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with colorectal cancer (PMID: 26086041). ClinVar contains an entry for this variant (Variation ID: 246221). 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). 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 arginine with histidine at codon 379 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 reported the mutant protein to be functional in yeast transactivation assays (IARC database and PMID: 12826609) and in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 26086041) as well as in individuals without cancer (PMID: 30287823, 32980694). This variant has been identified in 2/282792 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.