17-7675994-C-T

Position:

chr17-7675994-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The ENST00000269305.9(TP53):c.375G>A(p.Thr125=) variant causes a splice region, synonymous change involving the alteration of a non-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 benign outcome for this variant. 3/3 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 Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TP53
ENST00000269305.9 splice_region, synonymous

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22O:2

Conservation

PhyloP100: -0.0700

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-7675994-C-T is Pathogenic according to our data. Variant chr17-7675994-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675994-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.375G>A	p.Thr125=	splice_region_variant, synonymous_variant	4/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.375G>A	p.Thr125=	splice_region_variant, synonymous_variant	4/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

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:

1459934

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726262

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:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

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

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2023	Published functional studies demonstrate aberrant splicing, impaired transactivation, abnormal cellular localization, and loss of growth suppression ability (Warneford 1992, Varley 1997, Varley 2001, Kotler 2018, Lasham 2020, Pinto 2021); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 1467311, 28818333, 32504368, 34282142, 20501846, 22170717, 18511570, 24665023, 20522432, 26425688, 25525159, 24382691, 9242456, 1751410, 25584008, 1961027, 11420676, 23259501, 28347348, 29170254, 28026089, 28604612, 25945745, 29489754, 29979965, 30107858, 31439692, 32213968, 32888145, 30720243, 31105275, 32287321, 26582918, 33818021, 33011440, 33372952, 34539730, 33245408, 32427313, 34961499, 35512711, 37377903, 9681828, 30612635, 34887416, 34675114, Almeida2022[article], 35543639, 36428697, 15510160) -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 23, 2015	- -
not provided, no classification provided	in vitro	MutSpliceDB: a database of splice sites variants effects on splicing, NIH	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Hereditary cancer-predisposing syndrome

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 21, 2023	This variant alters the highly conserved, last nucleotide c.G in exon 4 of the TP53 gene and is predicted to abolish intron 4 splice donor site. This variant has been reported in individuals affected with Li-Fraumeni syndrome (PMID: 9242456, 11420676, 30107858), rhabdomyosarcoma (PMID: 24382691, 27501770, 33372952) and adrenocortical carcinoma (PMID: 22170717, 25584008), as well as in a family with Li-Fraumeni-like syndrome with an unusual spectrum of tumors at relatively late onset (PMID: 9681828). RT-PCR analysis of mRNA from the carriers in this family has detected no normally spliced transcript but three different aberrantly spliced transcripts from the mutant TP53 allele. All three aberrant transcripts are predicted to result in premature protein truncation (PMID: 9681828). Cells from the carriers showed increased sensitivity to radiation-induced chromosome damage in the G2 phase of the cell cycle, and decreased transient and permanent G1 arrest (PMID: 9681828). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, Catalan Institute of Oncology	May 22, 2023	c.375G>A variant affects a not conserved nucleotide, resulting in no amino acid change (phyloP=-0.12). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). Computational tools predict a significant impact on normal splicing (SSF, MaxEnt, NNSPLICE, GeneSplicer). They predict that the variant abolishes the consensus splicing donor site in intron 4. RNA studies have shown that this silent change affects TP53 function (internal data). The mutant allele generates a 200 bp deletion at the end of exon 4 (r.176_375del), causing a translational frameshift (p.Gly59Valfs*23) predicted to undergo NMD with evidence that the variant allele does not produce full-length transcript (PVS1 (RNA)). There is no evidence of a dominant negative effect or loss of function according to Giacomelli_2018 and transactivation assay is not performed (Kato_2003). This variant has been reported in 10 families/individuals, which awards 5.5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 9242456, 18511570, 20522432, 23259501, 25584008, 27501770) (PS4). It co-segregates in affected individuals (3 meiosis) (PMID: 9242456) (PP1). In addition, multiple clinical databases (ClinVar, LOVD) classified this variant as pathogenic. Based on the currently available information, c.375G>A is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 14, 2022	The c.375G>A pathogenic mutation (also known as p.T125T), located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 375. This nucleotide substitution does not change the threonine at codon 125. However, this change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. This mutation has been reported in numerous patients and families meeting Li-Fraumeni, Li-Fraumeni-like, and Chompret criteria (Varley JM et al. Cancer Res. 1997 Aug;57:3245-3252; Bougeard G et al. J. Med. Genet. 2008 Aug;45(8):535-8; Ruijs MW et al. J. Med. Genet. 2010 Jun;47(6):421-8; Mouchawar J et al. Cancer Res. 2010 Jun 15;70(12):4795-800; Foretova L et al. Klin. Onkol. 2010;23:388-400; Herrmann LJ et al. J. Clin. Endocrinol. Metab. 2012 Mar;97(3):E476-85; Hettmer S et al. Cancer. 2014 Apr 1;120(7):1068-75; Fortes FP et al. Braz. J. Med. Biol. Res. 2015 Jul;48(7):610-5; Gröbner SN et al. Nature. 2018 03;555(7696):321-327). Of note, this alteration is also designated as g.12299G>A in published literature. One study showed evidence of intron 3 retention in affected individuals with this mutation (Warneford SG et al. Cell Growth Differ. 1992 Nov;3(11):839-46) and this is supported by our internal RNA studies (Ambry internal data). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Li-Fraumeni syndrome

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 31, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 24, 2023	This variant alters the highly conserved, last nucleotide c.G in exon 4 of the TP53 gene and is predicted to abolish intron 4 splice donor site. This variant has been reported in individuals affected with Li-Fraumeni syndrome (PMID: 9242456, 11420676, 30107858), rhabdomyosarcoma (PMID: 24382691, 27501770, 33372952) and adrenocortical carcinoma (PMID: 22170717, 25584008), as well as in a family with Li-Fraumeni-like syndrome with an unusual spectrum of tumors at relatively late onset (PMID: 9681828). RT-PCR analysis of mRNA from the carriers in this family has detected no normally splice transcript but three different aberrantly spliced transcripts from the mutant TP53 allele. All three aberrant transcripts are predicted to result in premature protein truncation (PMID: 9681828). Cells from the carriers showed increased sensitivity to radiation-induced chromosome damage in the G2 phase of the cell cycle, and decreased transient and permanent G1 arrest (PMID: 9681828). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change affects codon 125 of the TP53 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TP53 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 1467311, 9242456, 11420676, 18511570, 21348412, 22170717, 24382691, 25584008, 25945745, 27501770). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177825). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in altered splicing and introduces a premature termination codon (PMID: 1467311, 11420676). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Li-Fraumeni syndrome 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 13, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 1467311, 11420676]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 1467311, 11420676, Myriad internal data]. -

TP53-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 19, 2022	The TP53 c.375G>A variant is not predicted to result in an amino acid change (p.=). This variant is predicted to strongly reduce the stregth of the neighboring splice donor site. This variant has been reported in several individuals with Li-Fraumeni and Li-Fraumeni-like syndrome (see for example, Warneford et al 1992. PubMed ID: 1467311; Wasserman JD et al 2015. PubMed ID: 25584008). These studies and others provide evidence that this variant segregates with disease in families and disrupts TP53 splicing. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is classified as pathogenic by several laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/177825/). We also clasify this variant as patogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Swedish National ChiCaP Initative, Genomic Medicine Sweden	May 01, 2024	- -

Adrenocortical carcinoma, hereditary

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 29, 2023

- -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

Glioma susceptibility 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Feb 28, 2020

- -

Rhabdomyosarcoma

Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Sep 01, 2020

- -

Malignant tumor of prostate

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

University Health Network, Princess Margaret Cancer Centre

Mar 19, 2021

- -

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

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Benign

0.87

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.58

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.58

Position offset: 0

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