ClinVar Genomic variation as it relates to human health

The NM_000546.6 :c.935C>G variant in TP53 is a missense variant predicted to cause substitution of threonine by serine at amino acid 312 (p.Thr312Ser). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000261663, SCV000184232). The filtering allele frequency is 0.0003446 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0123; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS1, BS3, BP4_moderate. (Bayesian Points: -14; VCEP specifications version 2.0; 7/24/2024)

This variant is denoted TP53 c.935C>G at the cDNA level, p.Thr312Ser (T312S) at the protein level, and results in the change of a Threonine to a Serine (ACC>AGC). This variant has been observed in at least one individual with a personal and/or family history suggestive of Li-Fraumeni syndrome (Bougeard 2008). Additionally, TP53 Thr312Ser has been identified in an individual with a head and neck cancer and in an individual with pancreatic cancer (Mafune 2015, Yang 2016). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Thr312Ser was observed at an allele frequency of 0.029% (7/24028) in individuals of African ancestry in large population cohorts (Lek 2016). TP53 Thr312Ser is not located within a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Thr312Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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.

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.

Variant summary: TP53 c.935C>G (p.Thr312Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251488 control chromosomes. The observed variant frequency is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), suggesting that the variant is benign. At least one functional study showed this variant has transcriptional activity similar to wild-type (PHANTM database). Nine clinical diagnostic laboratories and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (bening/likely benign n=4, including the expert panel; VUS n=6). Based on the evidence outlined above, the variant was classified as benign.

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).