17-7674263-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):c.700T>C(p.Tyr234His) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y234S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 4.46

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 18 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain 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 chr17-7674262-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 17-7674263-A-G is Pathogenic according to our data. Variant chr17-7674263-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.700T>C	p.Tyr234His	missense_variant	7/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.700T>C	p.Tyr234His	missense_variant	7/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 15, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 10229196, 10871862]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 29, 2019	The p.Y234H pathogenic mutation (also known as c.700T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 700. The tyrosine at codon 234 is replaced by histidine, an amino acid with some similar properties. This alteration was confirmed as a de novo alteration in a 10 month old patient with a rhabdomyosarcoma (Ambry internal data), and was reported in an individual with breast cancer at 33 and a leiomyosarcoma at 48 with loss of heterozygosity in the tumor (Mitchell G et al. PLoS ONE 2013 ; 8(7):e69026). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and deficient apoptosis induction (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul; 100(14):8424-9; Smith PD et al. Oncogene 1999 Apr; 18(15):2451-9). 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). Based on internal structural analysis, this variant may result in a decrease in structural stability (Cho Y et al. Science 1994 Jul; 265(5170):346-55). This amino acid position is well conserved in available vertebrate species. Based on the available evidence, p.Y234H is classified as a pathogenic mutation. -

Small cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 234 of the TP53 protein (p.Tyr234His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li Fraumeni syndrome (PMID: 23894400; Invitae). ClinVar contains an entry for this variant (Variation ID: 376691). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 8080050, 9525742, 10229196, 10871862, 11429705, 11896595, 12826609, 22710932). This variant disrupts the p.Tyr234 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12695689, 26556299, 28724667; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Glioblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Adrenal cortex carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Carcinoma of esophagus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Ovarian serous cystadenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of ovary Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Pancreatic adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Transitional cell carcinoma of the bladder Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hepatocellular carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.9	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;P;.;D;D;D;.;.;P;.;.;.;D
Vest4		0.88
MutPred		0.89		Gain of disorder (P = 0.0514);Gain of disorder (P = 0.0514);.;.;.;.;.;.;.;Gain of disorder (P = 0.0514);.;Gain of disorder (P = 0.0514);Gain of disorder (P = 0.0514);Gain of disorder (P = 0.0514);.;.;Gain of disorder (P = 0.0514);.;.;.;.;
MVP		0.96
MPC		1.9
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.67

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: rs864622237; hg19: chr17-7577581; COSMIC: COSV52694920; COSMIC: COSV52694920;