rs786201057

Positions:

• chr17-7675995-G-A
• chr17-7675995-G-C
• chr17-7675995-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T125P) has been classified as Likely 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:31 U: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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 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 chr17-7675995-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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-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: {Likely_pathogenic=8, Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.374C>T	p.Thr125Met	missense_variant, splice_region_variant	4/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.374C>T	p.Thr125Met	missense_variant, splice_region_variant	4/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32

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: 2 AN: 1459944 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726268

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: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74340

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:31 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:6

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	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. -
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, criteria provided, single submitter	curation	Sema4, Sema4	Nov 27, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 17, 2023	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, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -

not provided Pathogenic:2 Uncertain:1

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	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	TP53: PM2, PM5, PS4:Moderate -

Small cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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. -

Glioblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Adrenal cortex carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Carcinoma of esophagus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Papillary renal cell carcinoma type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Ovarian serous cystadenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Brainstem glioma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Acute myeloid leukemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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

- -

Pancreatic adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of brain Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Transitional cell carcinoma of the bladder Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hepatocellular carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	34
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	D
LIST_S2	Uncertain	0.90	D;D;.;.;.;D;D;.;D;D;D;D;D;T;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
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	D
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

Other links and lift over

dbSNP: rs786201057; hg19: chr17-7579313; COSMIC: COSV52673504; COSMIC: COSV52673504;