17-7675148-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6

The NM_000546.6(TP53):c.464C>G(p.Thr155Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 1.20

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15251175).

BP6

Variant 17-7675148-G-C is Benign according to our data. Variant chr17-7675148-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186179.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.464C>G	p.Thr155Ser	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.464C>G	p.Thr155Ser	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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

Cov.:

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 155 of the TP53 protein (p.Thr155Ser). This variant is present in population databases (rs786202752, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 186179). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 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. -

Oct 27, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with serine at codon 155 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have shown that this variant did not impact function in yeast transactivation assays (PMID: 12826609), human cell proliferation assays (PMID: 29979965), and human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with primary head and neck squamous cell carcinoma (PMID: 21159183). This variant has been identified in 1/31370 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Mar 22, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Mar 17, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified

Uncertain:1

Jun 24, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TP53 c.464C>G (p.Thr155Ser) results in a conservative amino acid change located in the p53 DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251290 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.464C>G has been reported in the literature in Malignant Peripheral Nerve Sheath tumors (MPNSTs) (Verdijk_2010 citing Mawrin_2002) and as a germline likely benign variant among individuals in gnomAD (Andrade_2019). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Co-occurrences with another pathogenic variant has been reported (PALB2 c.79G>T, p.27X; internal sample), providing supporting evidence for a benign role. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Carlsson_2009). The IARC database reports this as a functional variant based on overall transcriptional activity (TA) on 8 different promoters as measured in yeast assays by Kato et al. The following publications have been ascertained in the context of this evaluation (PMID: 30352134, 19558493, 20010306). ClinVar contains an entry for this variant (Variation ID: 186179). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Benign:1

Apr 01, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

1.0

DANN

Benign

0.20

DEOGEN2

Benign

0.29

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

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.68

T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.15

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

0.24

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

PrimateAI

Benign

0.33

PROVEAN

Benign

0.14

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

REVEL

Uncertain

0.42

Sift

Benign

0.54

T;T;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T;T;T

Sift4G

Benign

0.65

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.

Polyphen

0.033

B;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.;B;.

Vest4

0.13

MutPred

0.58

Gain of glycosylation at T155 (P = 0.0427);Gain of glycosylation at T155 (P = 0.0427);.;.;.;.;Gain of glycosylation at T155 (P = 0.0427);.;Gain of glycosylation at T155 (P = 0.0427);Gain of glycosylation at T155 (P = 0.0427);Gain of glycosylation at T155 (P = 0.0427);.;.;Gain of glycosylation at T155 (P = 0.0427);.;.;.;.;Gain of glycosylation at T155 (P = 0.0427);

MVP

0.78

MPC

0.59

ClinPred

0.037

GERP RS

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.23

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