17-7674917-T-C

Variant names:

• chr17-7674917-T-C
• rs1057520007
• NM_000546.6:c.614A>G

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.614A>G​(p.Tyr205Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y205N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.02
• Publications: 237 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 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 37 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 chr17-7674918-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 376686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 17-7674917-T-C is Pathogenic according to our data. Variant chr17-7674917-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 376681.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.614A>G	p.Tyr205Cys	missense	Exon 6 of 11	NP_000537.3
	TP53	NM_001126112.3		c.614A>G	p.Tyr205Cys	missense	Exon 6 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.614A>G	p.Tyr205Cys	missense	Exon 7 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.614A>G	p.Tyr205Cys	missense	Exon 6 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.614A>G	p.Tyr205Cys	missense	Exon 6 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.497A>G	p.Tyr166Cys	missense	Exon 5 of 10	ENSP00000478219.1

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 Pathogenic:2

Jan 10, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria was used: PM2_SUP; PS3; PS4_SUP; PP3_MOD; PS1; PP1

Aug 05, 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 cysteine, which is neutral and slightly polar, at codon 205 of the TP53 protein (p.Tyr205Cys). 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: 10922393, 21356188, 29324801). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 376681). 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, 16861262, 17724467, 20505364, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.

Li-Fraumeni syndrome 1 Pathogenic:1

Feb 15, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 7718482, 7761089, 15037740]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29324801, 21356188].

not provided Pathogenic:1

Nov 09, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29979965, 17724467, 15037740, 30224644, 15161705, 16861262, 7718482, 7761089, 15510160, 15541116, 10753186, 20505364, 23117049, 30840781, 30720243, 32817165, 34240179, 10922393, 21356188, 29324801)

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 22, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y205C pathogenic mutation (also known as c.614A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 614. The tyrosine at codon 205 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in families meeting classic Li Fraumeni syndome (LFS) criteria and LFS-like criteria (Portwine C et al. J Med Genet, 2000 Aug;37:E13; Plon SE et al. Cancer Genet, 2011 Jan;204:19-25; Stoltze U et al. PLoS One, 2018 Jan;13:e0190050). Another alteration at the same codon, p.Y205H (c.613T>C), has been detected in a patient meeting Chompret criteria (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (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 and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This amino acid position is highly 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.

TP53-related disorder Pathogenic:1

Apr 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TP53 c.614A>G variant is predicted to result in the amino acid substitution p.Tyr205Cys. This variant has been reported in multiple individuals with Li-Fraumeni syndrome (Portwine et al. 2000. PubMed ID: 10922393; Plon et al. 2011. PubMed ID: 21356188; Stoltze et al. 2018. PubMed ID: 29324801; Gao et al. 2020. PubMed ID: 32817165; Ceyhan-Birsoy et al. 2021. PubMed ID: 34240179). In vitro functional studies have demonstrated that this variant results in a loss of function with a dominant-negative effect on wild type p53 (Kato et al. 2003. PubMed ID: 12826609; Dearth et al. 2007. PubMed ID: 16861262; Kotler et al. 2018. PubMed ID: 29979965). This variant has not been reported in a large population database, indicating this variant is rare. This variant is listed in ClinVar as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/376681/). Of note, other missense variants at the same amino acid position (p.Tyr205Asp, p.Tyr205His) have also been reported as disease-causing in patients with Li-Fraumeni syndrome (Renaux-Petel et al. 2018. PubMed ID: 29070607; Kai et al. 2022. PubMed ID: 36219266). Taken together, this variant is interpreted as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.86		Gain of catalytic residue at L206 (P = 0.0401)
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.99
gMVP		0.86
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057520007; hg19: chr17-7578235; COSMIC: COSV52665440; COSMIC: COSV52665440;