ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.188C>T (p.Ala63Val) (rs372201428)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000663264 SCV001737942 likely benign Li-Fraumeni syndrome 1 2021-04-12 reviewed by expert panel curation 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 been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting: internal laboratory contributor (SCV000545312.6). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). In summary, TP53 c.188C>T (p.Ala63Val) 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, BP4.
GeneDx RCV000213047 SCV000211735 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing This variant is denoted TP53 c.188C>T at the cDNA level, p.Ala63Val (A63V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). 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 Ala63Val 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 Ala63Val occurs at a position that is not conserved and is located in the SH3 Domain (Bode 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether TP53 Ala63Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000161018 SCV000215136 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing The p.A63V variant (also known as c.188C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 188. The alanine at codon 63 is replaced by valine, an amino acid with similar properties. 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;100:8424-9). This amino acid position is not well conserved on limited sequence alignment. 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 alteration remains unclear.
Invitae RCV000467874 SCV000545312 uncertain significance Li-Fraumeni syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 63 of the TP53 protein (p.Ala63Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs372201428, ExAC 0.02%). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 182922). 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.
Counsyl RCV000663264 SCV000786495 uncertain significance Li-Fraumeni syndrome 1 2018-05-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000161018 SCV000908800 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264516 SCV001442710 uncertain significance not specified 2020-10-22 criteria provided, single submitter clinical testing Variant summary: TP53 c.188C>T (p.Ala63Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251036 control chromosomes. 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.188C>T in individuals affected with Li-Fraumeni Syndrome has been reported. Several publications however report this variant as likely benign among variants detected in the gnomAD/ExAC datasets (example, de Andrade_2017, de Andrade_2019). At least one publication reports experimental evidence evaluating an impact on protein function (example, Kato_2003). These results showed no damaging effect of this variant based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Five 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, some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.

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