ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.721T>G (p.Ser241Ala)

dbSNP: rs1057520002
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001045859 SCV001209733 pathogenic Li-Fraumeni syndrome 2023-06-24 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser241 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565143, 12826609, 20128691, 21343334, 23031740, 26585234, 26911350, 28975465). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 376665). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 241 of the TP53 protein (p.Ser241Ala).
Ambry Genetics RCV002374627 SCV002668762 pathogenic Hereditary cancer-predisposing syndrome 2023-02-25 criteria provided, single submitter clinical testing The p.S241A pathogenic mutation (also known as c.721T>G), located in coding exon 6 of the TP53 gene, results from a T to G substitution at nucleotide position 721. The serine at codon 241 is replaced by alanine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Additional studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, S241A disrupts a DNA interaction (Cho Y et al. Science, 1994 Jul;265:346-55). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc. RCV004022242 SCV004932449 likely pathogenic Li-Fraumeni syndrome 1 2024-02-16 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
All of Us Research Program, National Institutes of Health RCV001045859 SCV004830569 uncertain significance Li-Fraumeni syndrome 2023-11-30 flagged submission clinical testing

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