chr17-7674235-A-G

Variant names:

• chr17-7674235-A-G
• rs730882006
• NM_000546.6:c.728T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000546.6(TP53):​c.728T>C​(p.Met243Thr) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 9.32

Genes affected

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a turn (size 5) in uniprot entity P53_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.728T>C	p.Met243Thr	missense_variant	Exon 7 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.728T>C	p.Met243Thr	missense_variant	Exon 7 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 16, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M243T variant (also known as c.728T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 728. The methionine at codon 243 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in an individual with pineoblastoma diagnosed at age 14 (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). It has also been reported in patients with breast cancer (Park JS et al. Cancer Res Treat, 2022 Oct;54:1099-1110). This variant is located in the functionally critical DNA binding domain of the p53 protein and has been shown to be deficient in transcriptional transactivation in yeast-based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Jordan JJ, Mol. Cancer Res. 2010 May; 8(5):701-16). Studies conducted in human cell lines indicate this alteration is proficient 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). Crystal structure analysis indicates that M243 is one of the DNA contact residues of the p53 protein (Martin AC, Hum. Mutat. 2002 Feb; 19(2):149-64). Additional studies have indicated that this residue is important for the interaction between p53 and several of its interacting proteins, such as RAD51, BclXL and 53BP2 (Friedler A,J. Biol. Chem. 2005 Mar; 280(9):8051-9. Ma B, Phys Biol 2005 Jun; 2(2):S56-66). This amino acid position is well 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 Uncertain:1

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 243 of the TP53 protein (p.Met243Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li Fraumeni syndrome (PMID: 35974385). ClinVar contains an entry for this variant (Variation ID: 182936). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. 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. -

Adrenocortical carcinoma, hereditary Uncertain:1

Jun 21, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jul 29, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted TP53 c.728T>C at the cDNA level, p.Met243Thr (M243T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not been published as a germline pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, it has been reported as a somatic change in various tumor types including breast and soft tissue sarcoma according to the Catalogue of Somatic Mutations in Cancer. A prediction model based on sequence conservation and structural calculations predicted TP53 Met243Thr may impact binding with certain promoters (Carlsson 2009). TP53 Met243Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Met243Thr occurs at a position that is moderately conserved in mammals and is located in the DNA binding domain and interacts with HIPK1, ZNF385A, AXIN1, and 53BP2 SH3 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether TP53 Met243Thr is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.3	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G	Uncertain	0.0050	D;D;T;T;T;T;T;T;D;D;D;D;D;D;D;D;D;D;D;T;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;D;.;D;B;D;.;.;D;.;.;.;D
Vest4		0.48
MutPred		0.78		Loss of stability (P = 0.064);Loss of stability (P = 0.064);.;.;.;.;.;.;.;Loss of stability (P = 0.064);.;Loss of stability (P = 0.064);Loss of stability (P = 0.064);Loss of stability (P = 0.064);.;.;Loss of stability (P = 0.064);.;.;.;.;
MVP		0.93
MPC		0.41
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730882006; hg19: chr17-7577553; COSMIC: COSV52676629; COSMIC: COSV52676629;