Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000546.6(TP53):c.432G>T(p.Gln144His) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q144L) has been classified as Uncertain significance.
TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000546.6
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.928
Transitional cell carcinoma of the bladder Pathogenic:1
Likely pathogenic, no assertion criteria provided
literature only
Database of Curated Mutations (DoCM)
May 31, 2016
- -
Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided
literature only
Database of Curated Mutations (DoCM)
May 31, 2016
- -
Squamous cell carcinoma of the head and neck Pathogenic:1
Likely pathogenic, no assertion criteria provided
literature only
Database of Curated Mutations (DoCM)
May 31, 2016
- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Jul 05, 2019
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign in the germline to our knowledge; This variant is associated with the following publications: (PMID: 29979965, 12010886, 26619011) -
Loss of methylation at K139 (P = 0.1079);Loss of methylation at K139 (P = 0.1079);.;.;.;.;Loss of methylation at K139 (P = 0.1079);.;Loss of methylation at K139 (P = 0.1079);Loss of methylation at K139 (P = 0.1079);Loss of methylation at K139 (P = 0.1079);.;.;Loss of methylation at K139 (P = 0.1079);.;.;.;.;Loss of methylation at K139 (P = 0.1079);.;