rs786201057

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000546.6(TP53):c.374C>T(p.Thr125Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense, splice_region

Scores

Splicing: ADA: 0.9964

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16U:1O:1

Conservation

PhyloP100: 8.00

Variant links:

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 links:

TP53 (HGNC:):

TP53 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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

MetaRNN computational evidence supports a deleterious effect, 0.96

PP5

Variant 17-7675995-G-A is Pathogenic according to our data. Variant chr17-7675995-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 183748.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, other=1, Likely_pathogenic=11}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.374C>T	p.Thr125Met	missense_variant, splice_region_variant	4/11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.374C>T	p.Thr125Met	missense_variant, splice_region_variant	4/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459944

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726268

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:16Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 21, 2024	The p.T125M variant (also known as c.374C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 374. The threonine at codon 125 is replaced by methionine, an amino acid with similar properties. 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). However, studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no 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). This variant has been reported in multiple individuals with early-onset breast cancer (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8; Shirts BH et al. Genet. Med. 2016 10;18:974-81; Weitzel JN et al. Cancer. 2019 Aug;125:2829-2836) as well as in two individuals with childhood-onset adrenocortical carcinoma (Bougeard G et al. J. Clin. Oncol. 2015 Jul;33:2345-52). Another alteration at the same codon, p.T125R (c.374C>G), 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). In addition, several functional studies indicate that p.T125R is deleterious (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387; Menendez D et al. Mol. Cell. Biol. 2006 Mar;26:2297-308). The p.T125M 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 majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Likely pathogenic, criteria provided, single submitter	curation	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	May 14, 2021	Data included in classification: aGVGD: Class C65 and BayesDel score 0.5 (PP3_mod) 16 entries on cancer hotspots (PM1_mod) Bougeard et al. 2015: ACC in 2 children, Rana et al, 2019: 4 breast cancer cases and 1 sarcoma case, 14 observations in Ambry lab, 6 of which meet Chompret criteria (PS4_str) Data not included in classification: Conflicting functional evidence: Giacomelli et al. Nat Genet. 2018: NO DNE AND NO LOF Kato et al. PNAS 2003: Transactivation Class: non-functional Zerdoumi et al. HMG 2017: Dominant negative effect: ~75% decrease in p53 functionality score of lymphocytes compared to wild-type. Other classifications: Invitae (2020): Pathogenic; Ambry (2020) Counsyl (2016), Color (2015): Likely pathogenic; GeneDx (2019): VUS -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 27, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, Catalan Institute of Oncology	Jul 20, 2022	c.374C>T, located in exon 4 of the TP53 gene, is predicted to result in the substitution of Threonine by Methionine at codon 125, p.(Thr125Met). This variant is found in 1/31400 alleles at a frequency of 0.003% in the gnomAD v2.1.1 database, non-cancer dataset. 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: 0.5) (PP3_moderate). Functional studies show conflicting results. Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is no evidence of a dominant negative effect and no loss of function according to Giacomelli 2018 (PMID: 30224644). At least, this variant has been reported in 10 Chompret individuals, which awards 5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 26014290, 32457520) (PS4). It has been reported in ClinVar (1x as pathogenic, 26x as likely pathogenic, 1x as uncertain significance), LOVD (1x as likely pathogenic) and CancerHotspots (16 somatic observations, PM1). Based on the currently available information, c.374C>T is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 23, 2023	This missense variant replaces threonine with methionine at codon 125 DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. One RNA study showed use of a cryptic donor splice site and exon 4 skipping (PMID: 34675114). Functional studies have shown the mutant protein to be defective in transactivation activity (PMID: 10761705, 12826609, 28369373) and functional in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals meeting the Chompret criteria for Li-Fraumeni syndrome, including individuals affected with adrenocortical carcinoma (PMID: 26014290, 28369373; DOI:10.7759/cureus.24602) and individuals affected with early-onset breast cancer (PMID: 25503501, 34675114). This variant has been reported in additional individuals affected with breast cancer (PMID: 26845104, 31206626, 30128536, 34675114), ovarian cancer (PMID: 30216591), and bladder urothelial carcinoma (PMID: 34240179). This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position, p.Thr125Arg and p.Thr125Lys, are known to be disease-causing (ClinVar variation ID: 376667, 216465), indicating that threonine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 12, 2019	The best available variant frequency is uninformative. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2023	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; Published functional studies demonstrate significantly reduced transactivation in some studies but higher activity in others, and no loss of growth suppression activity (Kato et al., 2003, Perez et al., 2016, Giacomelli et al., 2018, Kotler et al., 2018, Pinto et al., 2021); Published functional studies investigating splicing found a low level of aberrant transcripts also present in wildtype controls, suggesting they may be naturally occurring isoforms (Pinto et al., 2021); Although this variant has been observed in individuals with a personal history of LFS-related cancers, such as adrenocortical carcinoma or early-onset breast cancer, it has not to our knowledge been reported in a family meeting classic LFS criteria or as a de novo variant. This variant has also been reported in unaffected adults and others whose histories are not consistent with LFS. (Bougeard et al., 2015, Maxwell et al., 2015, Shirts et al., 2016, de Andrade et al., 2017, Hu et al., 2018, Weber-Lasalle et al., 2018, Lu et al., 2019, Weitzel et al., 2019, Pinto et al., 2021).; This variant is associated with the following publications: (PMID: 27237367, 19046423, 21118481, 26849095, 26845104, 14559903, 20436704, 25503501, 10761705, 27998968, 27022024, 28369373, 26014290, 29319699, 12826609, 29079180, 30216591, 28861920, 30352134, 29922827, 30128536, 28472496, 30720243, 30840781, 31016814, 31206626, 31105275, 29979965, 30224644, 34675114, 15510160, 31794323, 35664418, 35426462) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	TP53: PM2, PM5, PS4:Moderate -

Li-Fraumeni syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 125 of the TP53 protein (p.Thr125Met). This variant is present in population databases (rs786201057, gnomAD 0.01%). This missense change has been observed in individuals with adrenocortical carcinoma, breast cancer, and/or Li-Fraumeni-associated cancers (PMID: 25503501, 26014290, 26845104; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183748). 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). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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, 16508005; Invitae). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant replaces threonine with methionine at codon 125 DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. One RNA study showed use of a cryptic donor splice site and exon 4 skipping (PMID: 34675114). Functional studies have shown the mutant protein to be defective in transactivation activity (PMID: 10761705, 12826609, 28369373) and functional in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals meeting the Chompret criteria for Li-Fraumeni syndrome, including individuals affected with adrenocortical carcinoma (PMID: 26014290, 28369373; DOI:10.7759/cureus.24602) and individuals affected with early-onset breast cancer (PMID: 25503501, 34675114). This variant has been reported in additional individuals affected with breast cancer (PMID: 26845104, 31206626, 30128536, 34675114), ovarian cancer (PMID: 30216591), and bladder urothelial carcinoma (PMID: 34240179). This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position, p.Thr125Arg and p.Thr125Lys, are known to be disease-causing (ClinVar variation ID: 376667, 216465), indicating that threonine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 09, 2024	Variant summary: TP53 c.374C>T (p.Thr125Met) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site. One predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. This variant is not found in the 1612278 control chromosomes (gnomAD). c.374C>T has been reported in the literature in heterozygous individuals affected with Li-Fraumeni Syndrome, ovariant cancer or breast cancer (Maxwell_2015, Shirts_2016, Zerdoumi_2017, Weber-Lassalle_2018, Kansuttiviwat_2024). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed a dominant negative effect (Zerdoumi_2017). The most pronounced variant effect results in 68% reduction in TP53 transcriptional activity in lymphocytes. The following publications have been ascertained in the context of this evaluation (PMID: 26014290, 38355628, 25503501, 26845104, 30216591, 28369373). ClinVar contains an entry for this variant (Variation ID: 183748). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Li-Fraumeni syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Oct 18, 2016

- -

Adrenocortical carcinoma, hereditary

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 19, 2023

- -

TP53-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Oct 01, 2024

- -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

D;D;.;D;.;.;.;.;.;.;D;.;D;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;.;.;.;D;D;.;D;D;D;D;D;T;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

2.9

.;.;.;M;.;M;M;M;.;.;M;.;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.0

D;D;.;D;.;.;D;D;.;.;D;.;D;.;D

REVEL

Pathogenic

0.93

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

0.75

MutPred

0.77

Gain of catalytic residue at T125 (P = 0.0283);Gain of catalytic residue at T125 (P = 0.0283);.;Gain of catalytic residue at T125 (P = 0.0283);.;Gain of catalytic residue at T125 (P = 0.0283);Gain of catalytic residue at T125 (P = 0.0283);Gain of catalytic residue at T125 (P = 0.0283);.;.;Gain of catalytic residue at T125 (P = 0.0283);.;Gain of catalytic residue at T125 (P = 0.0283);Gain of catalytic residue at T125 (P = 0.0283);Gain of catalytic residue at T125 (P = 0.0283);

MVP

0.98

MPC

1.7

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.84

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over