chr17-7675084-G-C

Position:

chr17-7675084-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000546.6(TP53):c.528C>G(p.Cys176Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C176R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 0.586

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7675086-A-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 17-7675084-G-C is Pathogenic according to our data. Variant chr17-7675084-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376572.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.528C>G	p.Cys176Trp	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.528C>G	p.Cys176Trp	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 20, 2024	The p.C176W variant (also known as c.528C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 528. The cysteine at codon 176 is replaced by tryptophan, an amino acid with highly dissimilar properties. 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 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). Another variant at the same codon, p.C176Y (c.527G>A), has been detected in at least one individual with classic Li-Fraumeni syndrome (LFS) tested by our laboratory (Ambry internal data), and was reported as a de novo alteration in an individual diagnosed with adrenocortical carcinoma at age 5 (Renaux-Petel M et al. J. Med. Genet. 2018 03;55(3):173-180). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -

TP53-related disorder

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 24, 2023	The TP53 c.528C>G variant is predicted to result in the amino acid substitution p.Cys176Trp. To our knowledge, this variant has not been reported in association with disorders as a germline variant in the literature. Functional studies showed that this variant results in ~11.31% transcriptional activity compared to wildtype TP53 protein (Kato et al. 2003. PubMed ID: 12826609; see data in http://mutantp53.broadinstitute.org/?query=p.C176W) and could alter downstream target gene expressions (Figure 4, Malcikova et al. 2009. PubMed ID: 19850740). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Different nucleotide substitutions affecting the same amino acid (p.Cys176Ser, p.Cys176Arg, p.Cys176Tyr, and p.Cys176Phe) have been reported to be associated with Li-Fraumeni syndrome-associated cancers (Human Gene Mutation Database). The c.528C>G (p.Cys176Trp) variant has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain to likely pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/376572). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 01, 2024	- -

Li-Fraumeni syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2020

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys176 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27622479, 12826609, 9572492). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect TP53 protein function (PMID: 12826609, 19850740). This variant has not been reported in the literature in individuals with TP53-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tryptophan at codon 176 of the TP53 protein (p.Cys176Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. -

Li-Fraumeni syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 14, 2024

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Ovarian neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

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

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.094

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

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

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

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

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.3

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

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-11

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

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0040

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;D;D;D;.

Polyphen

1.0

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

Vest4

0.96

MutPred

0.93

Gain of MoRF binding (P = 0.0186);Gain of MoRF binding (P = 0.0186);.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0186);.;Gain of MoRF binding (P = 0.0186);Gain of MoRF binding (P = 0.0186);Gain of MoRF binding (P = 0.0186);.;.;Gain of MoRF binding (P = 0.0186);.;.;.;.;

MVP

0.97

MPC

1.9

ClinPred

1.0

GERP RS

-1.3

Varity_R

1.0

gMVP

0.90

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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