NM_000546.6:c.725G>T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000546.6(TP53):c.725G>T(p.Cys242Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1AN: 1461830Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727230
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.C242F pathogenic mutation (also known as c.725G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 725. The cysteine at codon 242 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been identified in an Indian breast/ovarian cancer cohort (Singh J et al. Breast Cancer Res. Treat., 2018 Jul;170:189-196). This alteration has been reported as a germline alteration and as a somatic alteration in various tumors by the IARC TP53 database (Bouaoun L et al. IARC TP53 database [version 20, July 2019]. Hum. Mutat. 2016 Sep;37:865-76). This alteration is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: 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 alteration is located in the functionally critical DNA binding domain, and it is one of four amino acid residues required for zinc binding and protein stabilization (Cho Y et al. Science, 1994 Jul;265:346-55). 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. -
Ovarian neoplasm Pathogenic:1
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Li-Fraumeni syndrome Uncertain:1
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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965). 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: 376578). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 29470806). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 242 of the TP53 protein (p.Cys242Phe). -
Neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at