rs786204227

Positions:

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

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. BS3_Supporting BP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show a partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID:12826609, 30224644). In summary, TP53 c.1102C>T (p.His368Tyr) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BP4, BS3_Supporting. PM2_Supporting should not be considered conflicting evidence as the variant otherwise meets criteria for Likely Benign classification. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000039/MONDO:0007903/009

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense, splice_region
• Scores: Splicing: ADA: 0.00008561
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:1
• Conservation: PhyloP100: 1.87

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 Likely_benign. Variant got -1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.1102C>T	p.His368Tyr	missense_variant, splice_region_variant	11/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.1102C>T	p.His368Tyr	missense_variant, splice_region_variant	11/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 27, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 30, 2018	- -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2024

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). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". 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. -

Li-Fraumeni syndrome 1 Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Apr 19, 2021

This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show a partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). In summary, TP53 c.1102C>T (p.His368Tyr) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BP4, BS3_Supporting. PM2_Supporting should not be considered conflicting evidence as the variant otherwise meets criteria for Likely Benign classification. -

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	0.38	.;.;.;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	0.20	.;.;.;N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.23	.;.;.;N;.;N;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.92	.;.;.;T;.;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;B;.;B;.;.
Vest4		0.12
MutPred		0.18		.;.;.;Gain of phosphorylation at H368 (P = 0.0187);.;Gain of phosphorylation at H368 (P = 0.0187);.;.;
MVP		0.55
MPC		1.8
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204227; hg19: chr17-7573007;