ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.748C>G (p.Pro250Ala)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002391548 SCV002672696 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-19 criteria provided, single submitter clinical testing The p.P250A variant (also known as c.748C>G), located in coding exon 6 of the TP53 gene, results from a C to G substitution at nucleotide position 748. The proline at codon 250 is replaced by alanine, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and] is reported to have functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV003464485 SCV004206234 uncertain significance Adrenocortical carcinoma, hereditary 2023-09-08 criteria provided, single submitter clinical testing
Invitae RCV003509731 SCV004310912 uncertain significance Li-Fraumeni syndrome 2023-07-31 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). 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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 1759142). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 250 of the TP53 protein (p.Pro250Ala).

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