ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.221C>T (p.Ala74Val) (rs587781832)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000816275 SCV001429625 likely benign Li-Fraumeni syndrome 2020-08-11 reviewed by expert panel curation 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 >8 60+ year old females without a cancer diagnosis (BS2; Internal laboratory contributor. In summary, TP53 c.221C>T (p.Ala74Val) 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; BP4;BS2_Supporting.
Ambry Genetics RCV000130119 SCV000184950 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-07 criteria provided, single submitter clinical testing The p.A74V variant (also known as c.221C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 221. The alanine at codon 74 is replaced by valine, an amino acid with similar properties. It has been reported as a somatic mutation one time in an esophageal tumor, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). This variant is in the proline rich domain of the TP53 protein and was not found to have an effect on transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
GeneDx RCV000487230 SCV000570633 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted TP53 c.221C>T at the cDNA level, p.Ala74Val (A74V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has not, to our knowledge, been published in the literature as either a pathogenic or benign germline variant. This variant is reported as having functional transactivation activity in the International Agency for Research on Cancer (IARC) TP53 database based on functional studies by Kato et al. (2003). TP53 Ala74Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. TP53 Ala74Val is located in the SH3 Domain (Bode 2004). 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 Ala74Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000816275 SCV000956775 uncertain significance Li-Fraumeni syndrome 2020-08-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 74 of the TP53 protein (p.Ala74Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs587781832, ExAC 0.02%). This variant has not been reported as a germline variant in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 141547). An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). 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.
Color Health, Inc RCV000130119 SCV001736273 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-06 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 74 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 this variant protein is functional in yeast transactivation activity assay and in human cells (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/281908 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.

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