Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000546.6(TP53):c.731G>T(p.Gly244Val) 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. G244C) has been classified as Likely pathogenic.
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 Pathogenic. Variant got 12 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 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 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;
PM5
?
PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr17-7674232-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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, 0.993
PP5
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-7674232-C-A is Pathogenic according to our data. Variant chr17-7674232-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376601.Status of the report is criteria_provided_single_submitter, 1 stars.
Likely pathogenic, criteria provided, single submitter
clinical testing
Myriad Genetics, Inc.
Feb 16, 2024
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Malignant neoplasm of body of uterus Pathogenic:1
Likely pathogenic, no assertion criteria provided
literature only
Database of Curated Mutations (DoCM)
May 31, 2016
- -
Neoplasm of ovary Pathogenic:1
Likely pathogenic, no assertion criteria provided
research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Dec 01, 2018
- -
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided
literature only
Database of Curated Mutations (DoCM)
May 31, 2016
- -
Neoplasm of brain Pathogenic:1
Likely pathogenic, no assertion criteria provided
literature only
Database of Curated Mutations (DoCM)
May 31, 2016
- -
Neoplasm of the large intestine 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
Loss of disorder (P = 0.0852);Loss of disorder (P = 0.0852);.;.;.;.;.;.;.;Loss of disorder (P = 0.0852);.;Loss of disorder (P = 0.0852);Loss of disorder (P = 0.0852);Loss of disorder (P = 0.0852);.;.;Loss of disorder (P = 0.0852);.;.;.;.;