ENST00000619186.4:c.-51G>A

Variant names:

• chr17-7675185-C-T
• rs587782620
• ENST00000619186.4:c.-51G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The ENST00000619186.4(TP53):​c.-51G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TP53 ENST00000619186.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:2
• Conservation: PhyloP100: 1.26
• Publications: 126 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: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 17-7675185-C-T is Pathogenic according to our data. Variant chr17-7675185-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 142657.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.427G>A	p.Val143Met	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.427G>A	p.Val143Met	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00000205 AC: 3 AN: 1461872 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000416442), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000446 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:2

Jul 19, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with methionine at codon 143 in the DNA binding domain of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant impairs TP53 protein function in yeast transactivation assay and human cell growth assay (PMID: 9572492, 11222779, 12826609, 30224644). This variant has been reported in a child affected with choroid plexus carcinoma and her mother affected with early-onset breast cancer (PMID: 31278746). This family is affected with classic Li-Fraumeni syndrome with neuroblastoma, choroid plexus carcinoma, sarcoma and glioblastoma multiforme reported in the proband's siblings and maternal relatives. This variant has also been observed in an individual affected with early-onset breast cancer meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 23469205). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.428T>C (p.Val143Ala), is considered to be disease-causing (ClinVar Variation ID: 804214), suggesting that valine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Sep 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 143 of the TP53 protein (p.Val143Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 23469205, 33178583). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142657). Invitae Evidence Modeling incorporating data from in vitro 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, 30224644). This variant disrupts the p.Val143 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 19701813, 25318593, 29070607, 29979965, 30224644). 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. -

Li-Fraumeni syndrome 1 Pathogenic:1 Uncertain:1

Apr 11, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 31278746, 33178583]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Sep 09, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Adrenocortical carcinoma, hereditary Pathogenic:1

Mar 23, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast neoplasm Pathogenic:1

-

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1

Dec 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: demonstrates non-functional transactivation, impaired growth suppression ability and may exhibit a dominant negative effect (PMID: 9572492, 12826609, 30224644); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24590827, 11222779, 32164171, 23469205, 14559903, 9572492, 15541116, 29979965, 30720243, 30840781, 25847421, 20118236, 22768918, 31658756, 33057194, 35974385, 35982159, 33178583, 36349721, 34273903, 29070607, 30224644, 31278746, 12826609, 15510160) -

Choroid plexus papilloma;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931038:Familial pancreatic carcinoma;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5 Pathogenic:1

Apr 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 09, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V143M pathogenic mutation (also known as c.427G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 427. The valine at codon 143 is replaced by methionine, an amino acid with highly similar properties. This alteration was identified in an both a mother and child with breast cancer at 33 and choroid plexus carcinoma at age 1, respectively, and a family history consistent with classic Li Fraumeni syndrome (Gambale A et al. Clin. Genet. 2019 Oct;96:359-365). This alteration has also been reported in a Brazilian woman diagnosed with breast cancer at age 24 whose family history was not significant for TP53-associated cancers (Carraro DM et al. PLoS ONE. 2013; 8:e57581). The p.V143M alteration is positioned within the hydrophobic core of the beta-sandwich in the DNA binding domain of the TP53 protein (Bullock AN et al. Nat. Rev. Cancer. 2001 Oct; 1(1):68-76). 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). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well 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. -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The TP53 p.Val143Met variant was identified in 2 of 136 proband chromosomes (frequency: 0.01) from individuals with hepatocellular carcinoma and breast cancer (Carraro 2013, Janku 2015). The variant was identified in dbSNP (rs587782620) as “with pathogenic, uncertain significance allele” and ClinVar (interpreted as "uncertain significance" by Invitae and 2 others and "pathogenic" by A.C.Camargo Cancer Center). The variant was not identified in LOVD 3.0, UMD-LSDB, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In yeast cells expressing the variant, loss of transactivation activity was observed at 8 different promoters (Kato 2003). However, in additional yeast studies, the variant inhibited p53 transactivation at selected promoters, demonstrating only a partial loss of function effect (Epstein 1998, Kovvali 2001). The p.Val143 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D;D
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.;.
PhyloP100		1.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.2	N;N;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N;N;.
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;T;.;.;D
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D;.;.
Vest4		0.57
MutPred		0.78		Loss of catalytic residue at V143 (P = 0.1006);Loss of catalytic residue at V143 (P = 0.1006);.;.;.;.;Loss of catalytic residue at V143 (P = 0.1006);.;Loss of catalytic residue at V143 (P = 0.1006);Loss of catalytic residue at V143 (P = 0.1006);Loss of catalytic residue at V143 (P = 0.1006);.;.;Loss of catalytic residue at V143 (P = 0.1006);.;.;.;.;Loss of catalytic residue at V143 (P = 0.1006);.;
MVP		0.96
MPC		1.7
ClinPred		0.97	D
GERP RS		4.5
PromoterAI		0.0061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.66
gMVP		0.57
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs587782620; hg19: chr17-7578503; COSMIC: COSV52665025; COSMIC: COSV52665025;