17-7675995-G-C

Variant names:

• chr17-7675995-G-C
• rs786201057
• NM_000546.6:c.374C>G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000546.6(TP53):​c.374C>G​(p.Thr125Arg) variant causes a missense, splice region 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. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense, splice_region
• Scores: Splicing: ADA: 0.9957
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 8.00

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 17-7675995-G-C is Pathogenic according to our data. Variant chr17-7675995-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.374C>G	p.Thr125Arg	missense_variant, splice_region_variant	Exon 4 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.374C>G	p.Thr125Arg	missense_variant, splice_region_variant	Exon 4 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:3

Feb 13, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T125R variant (also known as c.374C>G) is located in coding exon 4 of the TP53 gene (NM_000546.5). This alteration results from a C to G substitution at nucleotide position 374. The threonine at codon 125 is replaced by arginine, an amino acid with similar properties. This variant was reported in individuals with Li Fraumeni syndrome in the UK (PMID:16508005‚ 20127978‚ 20407015). This variant submitted to ClinVar database (ID;376667) by five clinical laboratory and classified as Likely pathogenic/pathogenic .This amino acid position is highly conserved (PhyloP=7.8). Functional tests done for this variant confirm the pathogenicity (PMID: 30224644, 8023157, 12826609). In addition, this alteration is predicted to be deleterious by in silico analysis (as SIFT, CADD, M-CAP, Mutation taster and PolyPhen) . Based on these evidences this variant classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Jan 16, 2023

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.374C>G, located in exon 4 of the TP53 gene, is predicted to result in the substitution of Threonine by Lysine at codon 125, p.(Thr125Lys). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.59) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 2 Chompret individuals, which awards 1 point to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 20522432) (PS4_supporting). It has been reported in ClinVar, LOVD, CancerHotspots (6 somatic observations). Based on the currently available information, c.374C>G is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4. -

Nov 17, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T125R pathogenic mutation (also known as c.374C>G), located in coding exon 3 of the TP53 gene, results from a C to G substitution at nucleotide position 374. The threonine at codon 125 is replaced by arginine, an amino acid with similar properties. This mutation has been reported in several families meeting clinical criteria for Li Fraumeni syndrome (Morgan J et al Hum Mutat. 2010 Apr;31(4):484-91; Waszak SM et al. Lancet Oncol. 2018 06;19:785-798; Li JY et al. Int J Cancer. 2019 01;144:281-289). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-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 indicate this alteration is deficient 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). Other studies in mammalian cells showed that this alteration has decreased sensitivity to radiation, decreased suppression of colony growth, and reduced induction of apoptosis compared to wild type (Menendez D et al. Mol. Cell. Biol. 2006 Mar;26:2297-308). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome Pathogenic:1

Apr 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 125 of the TP53 protein (p.Thr125Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 18511570, 20127978, 20522432, 29753700; Invitae; externalcommunication). ClinVar contains an entry for this variant (Variation ID: 376667). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16508005, 17401428, 27533082). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Thr125 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 25503501, 26014290, 26845104). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Nov 22, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression ability (PMID: 12826609, 29979965, 30224644, 34675114, 27533082, 20407015, 12909720); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in several individuals with personal and family histories consistent with Li-Fraumeni syndrome tested at GeneDx and in published literature (PMID: 20522432, 34675114, 29753700); This variant is associated with the following publications: (PMID: 30840781, 20127978, 29979965, 15510160, 30224644, 33257846, 21121188, 30661751, 27533082, 26619011, 20407015, 12909720, 12826609, 34675114, 16508005, 26845104, 29753700, 29752822, 20522432, 18511570) -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;D;.;D;.;.;.;.;.;.;D;.;D;D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;.;.;D;D;.;D;D;D;D;D;T;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.3	.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.0	D;D;.;D;.;.;D;D;.;.;D;.;D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.;D;.;.;D;D;.;.;D;.;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;.;D;.
Polyphen		1.0	D;.;.;D;.;D;D;D;.;.;D;.;D;.;.
Vest4		0.85
MutPred		0.92		Loss of ubiquitination at K120 (P = 0.0299);Loss of ubiquitination at K120 (P = 0.0299);.;Loss of ubiquitination at K120 (P = 0.0299);.;Loss of ubiquitination at K120 (P = 0.0299);Loss of ubiquitination at K120 (P = 0.0299);Loss of ubiquitination at K120 (P = 0.0299);.;.;Loss of ubiquitination at K120 (P = 0.0299);.;Loss of ubiquitination at K120 (P = 0.0299);Loss of ubiquitination at K120 (P = 0.0299);Loss of ubiquitination at K120 (P = 0.0299);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.070		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: rs786201057; hg19: chr17-7579313; COSMIC: COSV52688693; COSMIC: COSV52688693;