17-7675145-C-G

Position:

• chr17-7675145-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000546.6(TP53):​c.467G>C​(p.Arg156Pro) variant causes a missense change. 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).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 4.69

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a strand (size 9) in uniprot entity P53_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 17-7675145-C-G is Pathogenic according to our data. Variant chr17-7675145-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 634768.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr17-7675145-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.467G>C	p.Arg156Pro	missense_variant	5/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.467G>C	p.Arg156Pro	missense_variant	5/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2024

The p.R156P variant (also known as c.467G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 467. The arginine at codon 156 is replaced by proline, an amino acid with dissimilar properties. This variant has been reported in a family with strong history of AML and other cancers (Zebisch A et al. Blood. 2016 11;128:2270-2272). This alteration has also been reported in an individual with a personal history of glioma/PNET and gliosarcoma with a family history of breast cancer and leukemia (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). 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 has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

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

- -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 10, 2022

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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 634768). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 27621308). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 156 of the TP53 protein (p.Arg156Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;T;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;T;D
Eigen	Benign	0.10
Eigen_PC	Benign	-0.080
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.0	N;N;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.082	T;T;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T;T;D
Sift4G	Benign	0.091	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D;.
Vest4		0.67
MutPred		0.69		Gain of glycosylation at R156 (P = 0.0155);Gain of glycosylation at R156 (P = 0.0155);.;.;.;.;Gain of glycosylation at R156 (P = 0.0155);.;Gain of glycosylation at R156 (P = 0.0155);Gain of glycosylation at R156 (P = 0.0155);Gain of glycosylation at R156 (P = 0.0155);.;.;Gain of glycosylation at R156 (P = 0.0155);.;.;.;.;Gain of glycosylation at R156 (P = 0.0155);
MVP		0.96
MPC		2.0
ClinPred		0.74	D
GERP RS		3.5
Varity_R		0.91
gMVP		0.82

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

Other links and lift over

dbSNP: rs371524413; hg19: chr17-7578463; COSMIC: COSV52710835; COSMIC: COSV52710835;