17-7675152-C-T

Position:

chr17-7675152-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2

The NM_000546.6(TP53):c.460G>A(p.Gly154Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,614,068 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:13O:1

Conservation

PhyloP100: 4.17

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 2 ACMG points.

PM1

In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.460G>A	p.Gly154Ser	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.460G>A	p.Gly154Ser	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251252

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135842

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727244

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000125

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2023	Observed in individuals with breast cancer, renal cancer, or hyperdiploid acute lymphocytic leukemia (Yang et al., 2017; Qian et al., 2018; Momozawa et al., 2018; Bittar et al., 2019; Dorling et al., 2021); Published functional studies are inconclusive: partially functional or competent transactivation, and growth suppression abilities comparable to wildtype (Kato et al., 2003; Shiraishi et al., 2004; Jordan et al., 2010; Giacomelli et al., 2018; Kotler et al., 2018); 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: 31321604, 28664506, 29979965, 28861920, 14559903, 20407015, 12826609, 30886117, 35008396, 30840781, 34234460, 33471991, 30287823, 15510160, 30224644, 29300620, 36479692, 37352403, 22768918) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	The TP53 c.460G>A; p.Gly154Ser variant (rs137852789) is reported in the literature in individuals affected with breast and renal cancer (Bittar 2019, Yang 2017). This variant is also reported in ClinVar (Variation ID: 133284). This variant is found in the non-Finnish European population with an allele frequency of 0.005% (6/129022 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.638). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bittar CM et al. TP53 variants of uncertain significance: increasing challenges in variant interpretation and genetic counseling. Fam Cancer. 2019 Oct;18(4):451-456. PMID: 31321604. Yang XR et al. Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia. Breast Cancer Res Treat. 2017 Oct;165(3):687-697. PMID: 28664506. -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 31, 2023	The p.G154S variant (also known as c.460G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 460. The glycine at codon 154 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a patient diagnosed with breast cancer at age 38 and in a patient diagnosed with renal cancer at age 40 (Yang XR et al. Breast Cancer Res.Treat. 2017 Oct;165(3):687-697; Bittar CM et al. Fam Cancer, 2019 10;18:451-456). This variant was also reported in 4/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is in the DNA binding domain of the TP53 protein and is reported to have partial loss of transactivation capacity and predicted to affect several p53 isoforms (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration remains proficient at 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 well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analyses. 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	Aug 21, 2023	This missense variant replaces glycine with serine at codon 154 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 the mutant protein to be partially functional in yeast transactivation assays (IARC database and PMID: 12826609, 20407015), functional in transcription activation assay in human cells (PMID: 33257846) and in human cell growth assay (PMID: 29979965). A different human cell growth assay was inconclusive regarding the variant impact on protein function (PMID: 30224644). This variant has been reported in three individuals affected with breast cancer (PMID: 28664506, 28861920, 30287823), in one individual affected each with renal cancer who met the Birch criteria for Li-Fraumeni syndrome testing (PMID: 31321604) and pediatric B-cell acute lymphoblastic leukemia (PMID: 29300620). This variant also has been detected in a breast cancer case-control meta-analysis in 4/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID TP53_010102). This variant has been identified in 6/282632 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. -

Li-Fraumeni syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 19, 2022	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 154 of the TP53 protein (p.Gly154Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with breast cancer, kidney cancer and acute lymphoblastic leukemia (PMID: 28664506, 29300620, 31321604; Invitae). ClinVar contains an entry for this variant (Variation ID: 133284). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 20407015, 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	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This missense variant replaces glycine with serine at codon 154 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 the mutant protein to be partially functional in yeast transactivation assays (IARC database and PMID: 12826609, 20407015), functional in transcription activation assay in human cells (PMID: 33257846) and in human cell growth assay (PMID: 29979965). A different human cell growth assay was inconclusive regarding the variant impact on protein function (PMID: 30224644). This variant has been reported in three individuals affected with breast cancer (PMID: 28664506, 28861920, 30287823), in one individual affected each with renal cancer who met the Birch criteria for Li-Fraumeni syndrome testing (PMID: 31321604) and pediatric B-cell acute lymphoblastic leukemia (PMID: 29300620). This variant also has been detected in a breast cancer case-control meta-analysis in 4/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID TP53_010102). This variant has been identified in 6/282632 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. -

Malignant tumor of urinary bladder

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Urology, Hospital Clinic de Barcelona

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 05, 2024

Variant summary: TP53 c.460G>A (p.Gly154Ser) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251252 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.460G>A has been reported in the literature in individuals affected with breast or renal cancer (e.g. Yang_2017, Bittar_2019). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The variant has been reported to be partially-functional based on overall transactivation activity (TA) on several different promoters as measured in yeast assays (Kato_2003, Jordan_2010), with significantly elevated transactivation activities at higher protein expression levels (Jordan_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20407015, 28664506, 31321604, 30224644,27463065). ClinVar contains an entry for this variant (Variation ID: 133284). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Li-Fraumeni syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Adrenocortical carcinoma, hereditary

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 15, 2023

- -

Choroid plexus papilloma;C0235974:Carcinoma of pancreas;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;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 10, 2022

- -

TP53-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

The TP53 c.460G>A variant is predicted to result in the amino acid substitution p.Gly154Ser. This variant was reported in an individual with breast cancer (Yang et al 2017. PubMed ID: 28664506) or an individual with renal cancer (Bittar CM et al 2019. PubMed ID: 31321604). This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Functional studies have been inconclusive regarding the impact of this missense change on TP53 function (Kato S et al 2003. PubMed ID: 12826609; Jordan JJ et al 2010. PubMed ID: 20407015; Kotler E et al 2018. PubMed ID: 29979965). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Sarcoma

Other:1

not provided, no classification provided

literature only

Laboratory of Translational Genomics, National Cancer Institute

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.71

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

Eigen

Benign

0.13

Eigen_PC

Benign

0.0019

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

1.6

.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.;.;.

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.5

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

REVEL

Uncertain

0.64

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

D;.;.;.;.;.;D;.;P;P;P;.;.;D;.;.;.;P;.

Vest4

0.37

MutPred

0.88

Gain of glycosylation at G154 (P = 0.0076);Gain of glycosylation at G154 (P = 0.0076);.;.;.;.;Gain of glycosylation at G154 (P = 0.0076);.;Gain of glycosylation at G154 (P = 0.0076);Gain of glycosylation at G154 (P = 0.0076);Gain of glycosylation at G154 (P = 0.0076);.;.;Gain of glycosylation at G154 (P = 0.0076);.;.;.;.;Gain of glycosylation at G154 (P = 0.0076);

MVP

0.95

MPC

0.85

ClinPred

0.90

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.88

gMVP

0.51

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