chr17-7674212-T-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.751A>C(p.Ile251Leu) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I251N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.751A>C | p.Ile251Leu | missense_variant | 7/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.751A>C | p.Ile251Leu | missense_variant | 7/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 27, 2016 | The I251L (ATC>CTC) missense variant in the TP53 gene, denoted c.751A>C at the cDNA level, has been reported previously in association with Li-Fraumeni syndrome (Wu et al., 2011). Additionally, the NHLBI ESP Exome Variant Server reports I251L was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Therefore, I251L is interpreted as a disease-causing variant. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jun 25, 2018 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 08, 2016 | The p.I251L variant (also known as c.751A>C), located in coding exon 6 of the TP53 gene, results from an A to C substitution at nucleotide position 751. The isoleucine at codon 251 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in the literature in one family with Li-Fraumeni syndrome (Wu CC et al. Hum. Genet. 2011 Jun; 129(6):663-73). This alteration is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This amino acid position is highly conserved in available vertebrate species. 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. - |
Li-Fraumeni syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Gastric cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | No evidence was found for rs730882007 (p.I251L) TP53 gene variant in stomach cancer so far. However, this variant has been observed in a male patient suffering from carcinoma of the stomach and in addition, this alteration is predicted to be deleterious by in silico analysis. - |
Ovarian neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at