rs786204227

Variant names:

• chr17-7669689-G-A
• rs786204227
• NM_000546.6:c.1102C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7669689-G-A
• chr17-7669689-G-C
• chr17-7669689-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. BP4 PM2_Supporting BS2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The NM_000546.6(TP53):c.1102C>T variant in TP53 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 368 (p.His368Tyr). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor). At least one individual with this variant was found to have a variant allele fraction of ≤35%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID:34906512, Internal lab contributor: Ambry). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = -0.2582; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). Due to conflicting evidence, this variant is classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PP4, PM2_Supporting, BP4_Moderate. (Bayesian Points: -1; VCEP specifications version 2.0; 1/16/2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000039/MONDO:0018875/009

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense, splice_region
• Scores: Splicing: ADA: 0.00008561
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 1.87
• Publications: 27 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.1102C>T	p.His368Tyr	missense_variant, splice_region_variant	Exon 11 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.1102C>T	p.His368Tyr	missense_variant, splice_region_variant	Exon 11 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:2

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 368 of the TP53 protein (p.His368Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 188342). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The tyrosine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609). 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.

Jan 16, 2025

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6(TP53):c.1102C>T variant in TP53 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 368 (p.His368Tyr). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor). At least one individual with this variant was found to have a variant allele fraction of ≤35%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: Ambry). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = -0.2582; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). Due to conflicting evidence, this variant is classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PP4, PM2_Supporting, BP4_Moderate. (Bayesian Points: -1; VCEP specifications version 2.0; 1/16/2025)

Hereditary cancer-predisposing syndrome Uncertain:2

Oct 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H368Y variant (also known as c.1102C>T), located in coding exon 10 of the TP53 gene, results from a C to T substitution at nucleotide position 1102. The histidine at codon 368 is replaced by tyrosine, an amino acid with similar properties. This variant is in the C-terminal regulatory domain of the TP53 protein and is reported to have a partial loss of transactivation capacity in a yeast based functional assay (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is poorly conserved and tyrosine is the reference amino acid in several mammalian species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

Jul 02, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces histidine with tyrosine at codon 368 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown that this variant is functional in yeast transcriptional transactivation studies and human cell growth suppression assays (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.34
DEOGEN2	Benign	0.0	.;.;.;T;.;T;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.64	T;T;.;.;.;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.047	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.0	.;.;.;N;.;N;.;.
PhyloP100		1.9
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.0	.;.;.;N;.;N;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;T;.;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Vest4		0.12
ClinPred		0.042	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.28
gMVP		0.17
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000086
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.030		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: rs786204227; hg19: chr17-7573007;