rs587780068

chr17-7675140-G-Achr17-7675140-G-Cchr17-7675140-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5

The NM_000546.6(TP53):c.472C>T(p.Arg158Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,070 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R158H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:8

Conservation

PhyloP100: 2.62

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain in NM_000546.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7675139-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 17-7675140-G-A is Pathogenic according to our data. Variant chr17-7675140-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127812.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.472C>T	p.Arg158Cys	missense_variant	5/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.472C>T	p.Arg158Cys	missense_variant	5/11	1	NM_000546.6	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251276

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000307

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TP53 p.Arg158Cys variant was identified in 1 of 206 proband chromosomes (frequency: 0.005) from an individual with adrenocortical cancer and testicular cancer (Herrmann 2011). The variant was also identified in the following databases: dbSNP (ID: rs587780068) as "With Likely pathogenic allele ", ClinVar (2x uncertain significance, 2x likely pathogenic), Clinvitae (3x uncertain significance), Cosmic (23x, confirmed somatic, in cancer of the large intestine, urinary tract, lung, endometrium, haematopoietic, and lymphoid system), IARC TP53 Database (21x somatic, partially functional transcriptional activity), and the UMD TP52 Mutation Database. The variant was not identified in GeneInsight-COGR, LOVD 3.0, or the Database of Germline p53 Mutations. The variant was identified in control databases in 2 of 246112 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European in 2 of 111580 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vitro yeast based functional assays have demonstrated this variant inhibits transactivation and is temperature sensitive (Monti 2003, Shiraishi 2004). Different missense substitutions at this codon have been determined to be pathogenic (Ruijis 2009, Wasserman 2015). The p.Arg158 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	Observed in individuals with breast cancer, glioblastoma, sarcoma, or adult-onset adrenocortical and testicular cancers (Herrmann 2012, Sun 2017, Meiss 2018, Huang 2018, Raad 2020, Sheng 2020); Published functional studies demonstrate partially functional transactivation and no impact on growth suppression, while others suggest a possible dominant-negative effect and reduced p53 functionality in patient cells (Marutani 1999, Kato 2003, Monti 2003, Giacomelli 2018, Kotler 2018, Raad 2020); 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; This variant is associated with the following publications: (PMID: 7700647, 25634010, 29625052, 30224644, 30840781, 22170717, 14559903, 17947339, 23200980, 24908601, 23531339, 25234657, 29979965, 28861920, 28724667, 12917626, 12826609, 30352134, 29958926, 15906354, 24326041, 10519380, 12909720, 30089713, 30128536, 30720243, 31105275, 33051313, 31119730, 29922827, 32817165, 30130155, 15510160) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 28, 2016	- -

Li-Fraumeni syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 158 of the TP53 protein (p.Arg158Cys). This variant is present in population databases (rs587780068, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 22170717, 28724667, 29625052, 31105275, 32817165). ClinVar contains an entry for this variant (Variation ID: 127812). Advanced modeling performed at Invitae incorporating data from internal and/or published 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 does not substantially affect TP53 function (PMID: 12826609, 12917626, 14559903, 29979965). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Oct 11, 2019	Data included in classification: UK family 1: Proband ACC at 11. Unaffected mother carries variant, maternal great uncle possible brain tumour and another maternal great-uncle in died in 20s (meets Chompret criteria). Literature/IARC case 1: ACC at 39 and testicular ca at 20. Herrmann et al, 2012 (PMID: 22170717, IARC ref 261) (meets Chompret criteria) (PS4_sup). The variants p.Arg158His and p.Arg158Leu at the same codon are considered likely pathogenic/pathogenic (PM5_mod). Variant is class 65 on AlignGVGD and Bayes del score 0.51 (PP3_mod). Data not included in classification: Variant observed in 2/125,638 gnomAD controls. Multiple reports of variant on IARC database with limited clinical information. Literature/IARC family 2: Proband breast cancer age 49 (Er+ve, PR +ve, Her2 -ve), fibrosarcoma at 59 in FDR, breast cancer at 50 in SDR, Lung cancer at 70 in SDR, cancer of unknown primary at 47 in SDR (Meiss et al. 2018, PMID: 29958926, IARC Ref 422). Kato et al. 2003 (PMID 12826609): Transactivation class partially functional, Giacomelli et al. 2018 (PMID 30224644) Combined model score: 123.6556. IARC classification: unclassified. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 14, 2023	The p.R158C variant (also known as c.472C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 472. The arginine at codon 158 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in the literature as being found in a patient diagnosed with adrenocortical carcinoma and secondary testicular cancer (Herrmann LJ et al. J. Clin. Endocrinol. Metab. 2012 Mar;97(3):E476-85), in several individuals with breast cancer (Sun J. et al. Clin Cancer Res. 2017 Oct;23(20):6113-6119; Meiss AE. et al. Hum Pathol. 2018 12;82:20-31), in a patient with glioblastoma (Huang KL. et al. Cell. 2018 04;173(2):355-370.e14), and in a patient with leiomyosarcoma (Raad S. et al. J Med Genet. 2021 12;58(12):796-805). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially 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 proficient at growth suppression, but 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 18, 2022	This missense variant replaces arginine with cysteine at codon 158 in the 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). Functional studies have shown that the mutant protein is functionally abnormal in a blood assay (PMID: 33051313), partially functional in yeast transactivation assays (IARC database and PMID: 12826609) and functional in human cell proliferation assay (PMID: 29979965). The variant impact on function was inconclusive in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with cutaneous carcinosarcoma with pathogenic co-variants (PMID: 33089535); in an individual affected with adrenocortical carcinoma with a family history of leukemia, lung cancer and adrenocortical carcinoma (PMID: 22170717); in an individual affected with breast cancer with a family history of fibrosarcoma, breast cancer and lung cancer (PMID: 29958926); and in at least two other individuals affected with breast cancer (PMID: 31119730, 33471991, 35820297). This variant has also been observed in individuals affected with pancreatic cancer and colorectal cancer (PMID: 23200980, 29844874). This variant has been identified in 2/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same position, p.Arg158His, is known to be pathogenic (Clinvar variation ID: 141963). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Lip and oral cavity carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Apr 30, 2019

- -

Li-Fraumeni syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

May 04, 2022

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 19, 2023

PM1, PP3, PS4_sup. According to the ClinGen ACMG TP53 v1.4.0 criteria we chose these criteria: PS4 (supporting pathogenic): Identified in multiple families fullfilling chompret criteria see ClinVar, PM1 (medium pathogenic): # of IARC somatic mutations (human tumors) 21; 5 somatic observations cancerhotspots.org, PP3 (medium pathogenic): BayesDel noAF noAF score 0.5145, Substitution GV GD PredictionR158C 0.00 179.53 Class C65, BS3 (supporting benign): Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20% and <=75% activity) AND: No evidence of DNE + no evidence of LOF from Giacomelli, et al data. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.51

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

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

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-7.7

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

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.97

MutPred

0.97

Loss of MoRF binding (P = 0.0175);Loss of MoRF binding (P = 0.0175);.;.;.;.;Loss of MoRF binding (P = 0.0175);.;Loss of MoRF binding (P = 0.0175);Loss of MoRF binding (P = 0.0175);Loss of MoRF binding (P = 0.0175);.;.;Loss of MoRF binding (P = 0.0175);.;.;.;.;Loss of MoRF binding (P = 0.0175);

MVP

1.0

MPC

1.9

ClinPred

1.0

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.85

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

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

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