rs763098116
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000546.6(TP53):c.830G>T(p.Cys277Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C277R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.830G>T | p.Cys277Phe | missense_variant | 8/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.830G>T | p.Cys277Phe | missense_variant | 8/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251308Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135834
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461856Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727230
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 04, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 277 of the TP53 protein (p.Cys277Phe). This variant is present in population databases (rs763098116, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 458567). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 9407971, 12826609, 19850740, 26070072, 29979965, 30224644). 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. - |
Li-Fraumeni syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 20, 2024 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 18524770, 27813088, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 23, 2023 | The p.C277F variant (also known as c.830G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 830. The cysteine at codon 277 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been shown to have a loss of transactivation activity in yeast based functional studies (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. U.S.A., 2003 Jul;100:8424-9; Kucab JE et al. DNA Repair (Amst.), 2016 Mar;39:21-33; Paget V et al. PLoS ONE, 2012 Feb;7:e30921). 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). Another alteration at the same codon, p.C277R (c.829T>C), has been detected an individual with a personal history of adrenocortical carcinoma and shown to segregate with disease in three affected family members in one family with early-onset breast cancer tested by our laboratory (Ambry internal data). This amino acid position is well conserved in available vertebrate species. The p.C277F alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD) non-cancer dataset. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
TP53-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 23, 2023 | The TP53 c.830G>T variant is predicted to result in the amino acid substitution p.Cys277Phe. To our knowledge, this variant has not been reported in the literature in association with TP53-related disease. Functional studies in vitro indicate that this variant affects protein function (see for example, Kato et al. 2003. PubMed ID: 12826609; Malcikova et al. 2009. PubMed ID: 19850740; Giacomelli AO et al. 2018. PMID: 30224644). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7577108-C-A). In ClinVar, it is classified as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/458567/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at