17-7675145-C-T

Position:

chr17-7675145-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PS4_ModerateBS3_SupportingBS2_Supporting

This summary comes from the ClinGen Evidence Repository: This variant has been reported in 4 probands meeting Revised Chompret criteria (PS4_Supporting; Internal laboratory and clinical contributors, SCV000186315.7). This variant has been observed in 4 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor, SCV000186315.7). Transactivation assays show a partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID:12826609, 30224644). In summary, the clinical significance of TP53 c.467G>A (p.Arg156His) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_moderate; BS2_supporting; BS4_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000216/MONDO:0007903/009

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:16B:1

Conservation

PhyloP100: 4.69

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 Uncertain_significance. Variant got 0 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.467G>A	p.Arg156His	missense_variant	5/11	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.467G>A	p.Arg156His	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251268

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135856

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:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000489

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:16Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 16, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 07, 2022	This missense variant replaces arginine with histidine at codon 156 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. A different variant affecting the same codon, c.467G>C (p.Arg156Pro), is considered to be disease-causing by one external laboratory (ClinVar variation ID: 634768), suggesting that Arg or similar amino acid at this position is important for the protein function. Functional studies in yeast and mammalian cells reported this variant protein to be partially functional to normal (PMID: 10435620, 12826609, 15781620, 21343334, 29979965, 30224644 and the IARC database). This variant has been reported in individuals with Li-Fraumeni syndrome with one or more additional TP53 missense covariants (PMID: 9667734, 10435620), Li-Fraumeni syndrome meeting Chompret criteria, astrocytoma, pediatric sarcoma (Nehoray et al, ASCO 2022), colorectal cancer (PMID: 26086041, 30092803, 30306255), breast cancer (PMID: 30287823, 31105275, 33471991; Nehoray et al, ASCO 2022) and in control individuals (PMID: 33471991). This variant has been identified in 4/251268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 27, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 07, 2024	The p.R156H variant (also known as c.467G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 467. The arginine at codon 156 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in the germline of a 17-year-old female with adrenocortical carcinoma (Juhlin CC et al. J. Clin. Endocrinol. Metab. 2015 Mar;100(3):E493-502). Additionally, this alteration was detected in the germline of a severely affected child with Li-Fraumeni syndrome (LFS) who also harbored two additional TP53 alterations and had a maternal family history consistent with LFS. Individual analysis of the two alterations found in cis (p.R156H and p.R267Q) showed only weak mutant phenotypes in functional studies, whereas the double mutant showed complete loss of transactivation activity and growth suppression. Authors suggest that p.R156H may cause a partial defect, with a second alteration needed on the same allele to fully inactivate the protein (Quesnel S et al. Oncogene. 1999 Jul;18(27):3970-8; Soussi T et al. Hum. Mutat. 2005 Jan;25(1):6-17). This same combination of variants (p.R156H and p.R267Q) was observed in a male diagnosed with sarcoma at age 40 and acute myeloid leukemia at age 42 (Swaminathan M et al. Cold Spring Harb Mol Case Stud 2019 02;5(1). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional or wild type-like transactivation activity in two different yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-279). Additional studies conducted in human cell lines show retained growth suppression (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 not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This alteration has been observed in numerous individuals who do not have a personal or family history that is consistent with or suggestive of TP53-associated disease (Ambry internal data). Based on the available evidence to date, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 22, 2024	Variant summary: TP53 c.467G>A (p.Arg156His) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the p53 protein. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251268 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.467G>A has been reported in the literature in a family with Li-Fraumeni Syndrome (LFS) spectrum tumors (Quesnel_1999), however additional TP53 variants were also present in the proband (both in cis and trans), and in other family members (in the mother another variant was found in cis). The variant was also reported in a patient affected with rhabdomyosarcoma (diagnosed at age 42), who met the criteria for LFS evaluation; this patient also harbored another co-occurring (phase unknown) TP53 variant (DiNardo_2016, Swaminathan_2019). The variant of interest was also reported (in absence of other variants) in individuals affected with different tumor phenotypes, including e.g. breast, colon, and adrenocortical carcinoma (Heymann_2010, Momozawa_2018, Rana_2019, Bonache_2018, Stjepanovic_2018, Juhlin_2015), however without strong evidence for causality. These data therefore do not allow clear conclusions about variant significance. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated conflicting evidence for functional impact, including decreased protein expression in mammalian cells (Quesnel_1999), and partial (Petitjean_2007), or intact transactivation capacity (Monti_2011) in yeast based assays. The following publications have been ascertained in the context of this evaluation (PMID: 23246812, 30306255, 27210295, 27895058, 16818505, 11782540, 22915647, 21059199, 26230955, 21519010, 20407015, 25490274, 27463065, 30327374, 30287823, 17606709, 21343334, 26585234, NCCN_AML, NCCN_MDS, NCCN_MPN, 25952993, 27276561, 17311302, 10435620, 31105275, 22186996, 27680515, 30092803, 30709875, 27959731, 30352134). ClinVar contains an entry for this variant (Variation ID: 127811). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 08, 2017	- -

Li-Fraumeni syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 06, 2024	This missense variant replaces arginine with histidine at codon 156 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. A different variant affecting the same codon, c.467G>C (p.Arg156Pro), is considered to be disease-causing by one external laboratory (ClinVar variation ID: 634768), suggesting that Arg or similar amino acid at this position is important for the protein function. Functional studies in yeast and mammalian cells reported this variant protein to be partially functional to normal (PMID: 10435620, 12826609, 15781620, 21343334, 29979965, 30224644 and the IARC database). This variant has been reported in individuals with Li-Fraumeni syndrome with one or more additional TP53 missense covariants (PMID: 9667734, 10435620), Li-Fraumeni syndrome meeting Chompret criteria, astrocytoma, pediatric sarcoma (Nehoray et al, ASCO 2022), colorectal cancer (PMID: 26086041, 30092803, 30306255), breast cancer (PMID: 30287823, 31105275, 33471991; Nehoray et al, ASCO 2022) and in control individuals (PMID: 33471991). This variant has been identified in 4/251268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 156 of the TP53 protein (p.Arg156His). This variant is present in population databases (rs371524413, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of TP53-related conditions and/or TP53-related conditions (PMID: 9667734, 10435620, 21343334, 26086041, 27210295, 28477317, 30092803; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127811). 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: 10435620, 12826609, 17311302, 17606709, 21343334, 29979965, 30224644). 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. -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Squamous cell carcinoma of the head and neck

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	case-control	Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo	-	- -

Li-Fraumeni syndrome 1

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Feb 22, 2021

This variant has been reported in 4 probands meeting Revised Chompret criteria (PS4_Supporting; Internal laboratory and clinical contributors, SCV000186315.7). This variant has been observed in 4 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor, SCV000186315.7). Transactivation assays show a partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.467G>A (p.Arg156His) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_moderate; BS2_supporting; BS4_supporting. -

Adrenocortical carcinoma, hereditary

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 05, 2024

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 04, 2024

Reported in individuals with Li-Fraumeni spectrum tumors, but some had other TP53 variants identified as well, making it difficult to assess the individual contribution of TP53 Arg156His to their phenotype; in addition this variant was also identified in unaffected relatives and controls (PMID: 10435620, 21059199, 25490274, 27210295, 28477317, 30092803, 30287823, 34863587, 33471991, 34326862); 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: 11793474, 21343334, 25637381, 27923552, 28477317, 30709875, 31948886, 17606709, 15580553, 17133269, 9667734, 25490274, 17318340, 27146902, 17541742, 27210295, 29077256, 29979965, 28861920, 28152038, 25299233, 21348641, 10519380, 17311302, 12826609, 30092803, 25184754, 26086041, 21666498, 30089713, 21059199, 30720243, 30840781, 30306255, 29625052, 31105275, 32998877, 33257846, 10435620, 33932062, 15781620, 35371985, 26230955, 34273903, 30352134, 27463065, 30327374, 27276561, 27895058, 26585234, 22186996, 16818505, 23246812, 21519010, 20407015, 11782540, 30224644, 32566746, 30816478, 27959731, 25952993, 22915647, 34863587, 30287823, 36451132, 35306447, 35709138, 33471991, 27680515, 35534704, 36243179, 34326862, 35980532, 15510160, 39133963, 39256447) -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 06, 2024

- -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jun 16, 2020

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

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

Eigen

Benign

0.0038

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.83

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

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.79

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

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

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

N;N;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.017

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

Sift4G

Uncertain

0.049

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

Polyphen

1.0

D;.;.;.;.;.;D;.;D;B;D;.;.;D;.;.;.;D;.

Vest4

0.38

MVP

0.96

MPC

1.8

ClinPred

0.70

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.39

gMVP

0.37

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

Other links and lift over