17-7675214-A-G

Position:

• chr17-7675214-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001126115.2(TP53):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_001126115.2 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.32

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7675214-A-G is Pathogenic according to our data. Variant chr17-7675214-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.398T>C	p.Met133Thr	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.398T>C	p.Met133Thr	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 26, 2023	The p.M133T pathogenic mutation (also known as c.398T>C), located in coding exon 4 of the TP53 gene, results from a T to C substitution at nucleotide position 398. The methionine at codon 133 is replaced by threonine, an amino acid with some similar properties. This alteration was reported in a large family with Li-Fraumeni syndrome (LFS) and was found to segregate with LFS spectrum tumors in nine affected family members (Law J et al. Cancer Res. 1991 Dec;51:6385-7). In addition, this alteration was detected in a second large pedigree with several LFS tumors, and was found to segregate with disease in three affected family members (Shay J et al. Mol. Cell. Biol. 1995 Jan;15:425-32). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (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 (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). The p.M133T alteration was also shown to have less than 25% binding capacity to multiple response elements when compared to wild type TP53 (Malcikova J et al. Biol. Chem.;391:197-205). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science 1994 Jul; 265(5170):346-55; Ambry internal data). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 09, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects TP53 protein function (PMID: 20128691, 12826609, 21343334, 29979965, 30224644). This variant has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 1933902, 10477429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12357). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 133 of the TP53 protein (p.Met133Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2022

Segregates with disease in many affected individuals with LFS-associated cancers from two large families in published literature (Law et al., 1991; Shay et al., 1995; Hung et al., 1999); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: impaired DNA binding, lack of transcriptional activation, loss of growth suppression activities, and a dominant-negative effect (Kato et al., 2003; Malcikova et al., 2010; Monti et al., 2011; Jagosova et al., 2012; Giacomelli et al., 2018; Kotler et al., 2018); This variant is associated with the following publications: (PMID: 22507745, 30224644, 17606709, 30840781, 21311097, 21317445, 21305319, 31105275, 22710932, 21343334, 20128691, 12826609, 29979965, 10477429, 1933902, 7799951, 15510160, 34273903) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D;D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D;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	0.0	.;.;.;.;.;.;N;.;N;N;N;.;.;N;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.;D
Polyphen		0.67	P;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.;B;.;.
Vest4		0.72
MutPred		0.92		Loss of catalytic residue at M133 (P = 0.0062);Loss of catalytic residue at M133 (P = 0.0062);.;.;.;.;Loss of catalytic residue at M133 (P = 0.0062);.;Loss of catalytic residue at M133 (P = 0.0062);Loss of catalytic residue at M133 (P = 0.0062);Loss of catalytic residue at M133 (P = 0.0062);.;.;Loss of catalytic residue at M133 (P = 0.0062);.;.;.;.;Loss of catalytic residue at M133 (P = 0.0062);.;
MVP		0.99
MPC		0.97
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.62

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: rs28934873; hg19: chr17-7578532; COSMIC: COSV52795528; COSMIC: COSV52795528;