chr17-7674205-G-A

Variant names:

• chr17-7674205-G-A
• rs1555525465
• NM_000546.6:c.758C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_000546.6(TP53):​c.758C>T​(p.Thr253Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T253P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 1.56
• Publications: 1 publications found

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]

TP53 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 13 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7674206-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 827132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 17-7674205-G-A is Pathogenic according to our data. Variant chr17-7674205-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 837688.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.758C>T	p.Thr253Ile	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.758C>T	p.Thr253Ile	missense_variant	Exon 7 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:1

Feb 16, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 14559903]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Li-Fraumeni syndrome Uncertain:1

Jul 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 253 of the TP53 protein (p.Thr253Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 837688). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 14559903). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T253I variant (also known as c.758C>T), located in coding exon 6 of the TP53 gene, results from a C to T substitution at nucleotide position 758. The threonine at codon 253 is replaced by isoleucine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). 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, and isoleucine is the reference amino acid in other 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	0.96
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T;T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.71	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	Benign	1.6	.;.;.;.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.
PhyloP100		1.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.2	N;N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N
REVEL	Pathogenic	0.79
Sift	Benign	0.36	T;T;.;.;.;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;.;.;.;.;.;.;.;.;D;.;D;B;D;.;.;D;.;.;.
Vest4		0.32
MutPred		0.62		Loss of disorder (P = 0.0845);Loss of disorder (P = 0.0845);.;.;.;.;.;.;.;Loss of disorder (P = 0.0845);.;Loss of disorder (P = 0.0845);Loss of disorder (P = 0.0845);Loss of disorder (P = 0.0845);.;.;Loss of disorder (P = 0.0845);.;.;.;
MVP		0.89
MPC		0.40
ClinPred		0.85	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.60

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

Other links and lift over

dbSNP: rs1555525465; hg19: chr17-7577523; COSMIC: COSV52863408; COSMIC: COSV52863408;