ClinVar Genomic variation as it relates to human health

Transactivation assays show retained 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). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting, internal laboratory contributor). In summary, TP53 c.949C>A (p.Gln317Lys) 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, BS2_supporting, BP4.

This variant is denoted TP53 c.949C>A at the cDNA level, p.Gln317Lys (Q317K) at the protein level, and results in the change of a Glutamine to a Lysine (CAG>AAG). Kantorova et al. (2014) observed this variant in an individual with chronic lymphocytic leukemia and concluded that it preserves transcriptional activity in an in vitro-based functional assay. Additionally, TP53 Gln317Lys is reported as functional by in the International Agency for Research on Cancer TP53 database based on transactivation assays completed by Kato et al. (2003). TP53 Gln317Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Gln317Lys occurs at a position that is not conserved and is located within a nuclear localization signal (Shaulsky 1990, Pessoa 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether TP53 Gln317Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

This missense variant replaces glutamine with lysine at codon 317 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 that the mutant protein retains normal function (PMID 12826609, 25527155, 30224644). This variant has been reported in an individual affected with chronic lymphocytic leukemia (PMID 25527155). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 2/282868 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 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.

In the published literature, this variant has been reported in individuals affected with ovarian cancer (PMID: 30441849 (2018)) and chronic lymphocytic leukemia (PMID: 25527155 (2015)). Functional studies indicate that this variant retains binding and transcriptional activity (PMID: 12826609 (2003), 30224644 (2018)). The frequency of this variant in the general population, 0.0000071 (2/282868 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.

This missense variant replaces glutamine with lysine at codon 317 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 that the mutant protein retains normal function (PMID 12826609, 25527155, 30224644). This variant has been reported in an individual affected with chronic lymphocytic leukemia (PMID 25527155). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 2/282868 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.

TP53: BP4, BS3:Supporting

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).