rs1555525012
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000546.6(TP53):c.925C>T(p.Pro309Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P309L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.925C>T | p.Pro309Ser | missense_variant | 9/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.925C>T | p.Pro309Ser | missense_variant | 9/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727240
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 26, 2023 | This missense variant replaces proline with serine at codon 309 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant to be functional in yeast trancriptional activation assays and human cell growth suppression assays (PMID: 12826609, 30224644). This variant has been reported in individuals affected with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia in the literature (PMID: 15784129, 29300620). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 14, 2024 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Li-Fraumeni syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | This missense variant replaces proline with serine at codon 309 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant to be functional in yeast trancriptional activation assays and human cell growth suppression assays (PMID: 12826609, 30224644). This variant has been reported in individuals affected with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia in the literature (PMID: 15784129, 29300620). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 309 of the TP53 protein (p.Pro309Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with leukemias (PMID: 15784129, 29300620). ClinVar contains an entry for this variant (Variation ID: 458575). 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 with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at