17-7674257-A-G

Variant names:

• chr17-7674257-A-G
• rs587782289
• NM_000546.6:c.706T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):​c.706T>C​(p.Tyr236His) variant causes a missense 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y236N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.31
• Publications: 131 publications found

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 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 51 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 32 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 chr17-7674256-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376693.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 17-7674257-A-G is Pathogenic according to our data. Variant chr17-7674257-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 216469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.706T>C	p.Tyr236His	missense	Exon 7 of 11	NP_000537.3
	TP53	NM_001126112.3		c.706T>C	p.Tyr236His	missense	Exon 7 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.706T>C	p.Tyr236His	missense	Exon 8 of 12	NP_001394191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.706T>C	p.Tyr236His	missense	Exon 7 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.706T>C	p.Tyr236His	missense	Exon 7 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.589T>C	p.Tyr197His	missense	Exon 6 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:1

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 236 of the TP53 protein (p.Tyr236His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TP53-related conditions (external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 216469). 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: 12826609, 29979965). For these reasons, this variant has been classified as Pathogenic.

Li-Fraumeni syndrome 1 Pathogenic:1

Feb 16, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 25, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y236H variant (also known as c.706T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 706. The tyrosine at codon 236 is replaced by histidine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and deficient growth suppression in functional studies (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). In addition, this variant has been determined to be the result of a de novo mutation or germline mosaicism in one family within our clinical cohort (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). Another missense alteration at this codon (p.Y236C) has also been reported in a Li-Fraumeni syndrome patient and functional assays have shown it to be a severely-deficient, dominant-negative mutation (Rines R et al. Carcinogenesis. 1998 Jun;19(6):979-84; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9). Based on the available evidence, p.Y236H is classified as a pathogenic mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.90		Gain of disorder (P = 0.0333)
MVP		0.94
MPC		0.43
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.96
gMVP		0.69
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587782289; hg19: chr17-7577575; COSMIC: COSV52783032; COSMIC: COSV52783032;