17-7675176-A-C

Position:

• chr17-7675176-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. BP4 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). This variant has been reported in 1 proband meeting Classic LFS criteria (PS4_Supporting; NIH). In summary, the clinical significance of TP53 c.436T>G (p.Trp146Gly) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PS4_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000190/MONDO:0007903/009

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 1.07

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 Uncertain_significance. Variant got 1 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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	c.436T>G	p.Trp146Gly	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.436T>G	p.Trp146Gly	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: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome 1 Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Sep 04, 2020

This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). This variant has been reported in 1 proband meeting Classic LFS criteria (PS4_Supporting; NIH). In summary, the clinical significance of TP53 c.436T>G (p.Trp146Gly) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PS4_Supporting, BP4. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The p.W146G variant (also known as c.436T>G), located in coding exon 4 of the TP53 gene, results from a T to G substitution at nucleotide position 436. The tryptophan at codon 146 is replaced by glycine, an amino acid with highly dissimilar properties. 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). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Uncertain	0.77	D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D;D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.82	T;T;D;D;D;.;.;.;T;T;.;T;T;T;T;D;D;T;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	N;N;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;D;D;.
REVEL	Uncertain	0.54
Sift	Benign	0.10	T;T;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T;T;D;.
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;T
Polyphen		0.93	P;.;.;.;.;.;B;.;P;B;P;.;.;B;.;.;.;B;.;.
Vest4		0.47
MutPred		0.61		Gain of disorder (P = 0.0062);Gain of disorder (P = 0.0062);.;.;.;.;Gain of disorder (P = 0.0062);.;Gain of disorder (P = 0.0062);Gain of disorder (P = 0.0062);Gain of disorder (P = 0.0062);.;.;Gain of disorder (P = 0.0062);.;.;.;.;Gain of disorder (P = 0.0062);.;
MVP		0.97
MPC		2.1
ClinPred		0.59	D
GERP RS		0.44
Varity_R		0.74
gMVP		0.53

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: rs786203064; hg19: chr17-7578494; COSMIC: COSV52726362; COSMIC: COSV52726362;