17-7675215-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000504937.5(TP53):c.1A>G(p.Met1?) variant causes a start lost 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 ENST00000504937.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.397A>G	p.Met133Val	missense_variant	5/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.397A>G	p.Met133Val	missense_variant	5/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250826 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135576

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 23, 2019

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. A different missense substitution at this codon (p.Met133Thr) has been reported in families affected with Li-Fraumeni syndrome (PMID: 1933902, 17606709), and it has been shown to impair the transcriptional transactivation activity of the TP53 protein in experimental studies (PMID: 12826609, 17606709, 20128691, 21343334). This suggests that the methionine residue is critical for TP53 protein function and that other missense substitutions at this position may also be damaging. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 528246). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 133 of the TP53 protein (p.Met133Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Benign	0.40	T;T;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;T;T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;T;D;D;D;T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationTaster	Benign	0.51	N;N;N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.0	N;N;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N;N;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.028	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.
Sift4G	Uncertain	0.033	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.;D
Polyphen		0.041	B;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.;B;.;.
Vest4		0.39
MutPred		0.82		Loss of catalytic residue at M133 (P = 9e-04);Loss of catalytic residue at M133 (P = 9e-04);.;.;.;.;Loss of catalytic residue at M133 (P = 9e-04);.;Loss of catalytic residue at M133 (P = 9e-04);Loss of catalytic residue at M133 (P = 9e-04);Loss of catalytic residue at M133 (P = 9e-04);.;.;Loss of catalytic residue at M133 (P = 9e-04);.;.;.;.;Loss of catalytic residue at M133 (P = 9e-04);.;
MVP		0.91
MPC		0.67
ClinPred		0.19	T
GERP RS		-0.051
Varity_R		0.46
gMVP		0.30

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: rs1057280220; hg19: chr17-7578533; COSMIC: COSV53106978; COSMIC: COSV53106978;