17-7674236-T-A

Position:

• chr17-7674236-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000546.6(TP53):​c.727A>T​(p.Met243Leu) 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M243T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.672

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 6 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 12 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.727A>T	p.Met243Leu	missense_variant	7/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.727A>T	p.Met243Leu	missense_variant	7/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 19, 2023

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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 1758050). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 243 of the TP53 protein (p.Met243Leu). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The p.M243L variant (also known as c.727A>T), located in coding exon 6 of the TP53 gene, results from an A to T substitution at nucleotide position 727. The methionine at codon 243 is replaced by leucine, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Additional studies have indicated that this residue, M243, is important for the interaction between p53 and several of its interacting proteins, such as RAD51, BclXL and 53BP2 (Friedler A et al. J. Biol. Chem. 2005 Mar; 280(9):8051-9. Ma B et al. Phys Biol. 2005 Jun; 2(2):S56-66). Other studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.55	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T;T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;D;T;D;T;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	N;N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0060	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G	Uncertain	0.020	D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;.
Polyphen		0.93	P;.;.;.;.;.;.;.;.;D;.;D;B;D;.;.;D;.;.;.;D
Vest4		0.37
MutPred		0.75		Gain of catalytic residue at M243 (P = 0.1414);Gain of catalytic residue at M243 (P = 0.1414);.;.;.;.;.;.;.;Gain of catalytic residue at M243 (P = 0.1414);.;Gain of catalytic residue at M243 (P = 0.1414);Gain of catalytic residue at M243 (P = 0.1414);Gain of catalytic residue at M243 (P = 0.1414);.;.;Gain of catalytic residue at M243 (P = 0.1414);.;.;.;.;
MVP		0.90
MPC		0.37
ClinPred		0.83	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.42

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: rs786203117; hg19: chr17-7577554; COSMIC: COSV52713381; COSMIC: COSV52713381;