17-7675232-G-T

Variant names:

• chr17-7675232-G-T
• rs730881999
• NM_000546.6:c.380C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PS4_Supporting PM1 PS3 PP3_Moderate PP1

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 65 (PP3_Moderate). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is an in vitro proliferation assay demonstrating loss of function (PS3; PMID:12826609, PMID:25584008). This variant has been reported in 2 probands meeting Chompret criteria (PS4; internal laboratory contributors). This variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed (PP1; internal laboratory contributor). In summary, TP53 c.380C>A (p.Ser127Tyr) meets criteria to be classified as Pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, PM1, PS3, PS4_Supporting, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA397843908/MONDO:0007903/009

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 9.95
• Publications: 172 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 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

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.380C>A	p.Ser127Tyr	missense	Exon 5 of 11	NP_000537.3
	TP53	NM_001126112.3		c.380C>A	p.Ser127Tyr	missense	Exon 5 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.380C>A	p.Ser127Tyr	missense	Exon 6 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.380C>A	p.Ser127Tyr	missense	Exon 5 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.380C>A	p.Ser127Tyr	missense	Exon 5 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.263C>A	p.Ser88Tyr	missense	Exon 4 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2

Feb 13, 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].

Apr 20, 2021

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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 65 (PP3_Moderate). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is an in vitro proliferation assay demonstrating loss of function (PS3; PMID: 12826609, PMID: 25584008). This variant has been reported in 2 probands meeting Chompret criteria (PS4; internal laboratory contributors). This variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed (PP1; internal laboratory contributor). In summary, TP53 c.380C>A (p.Ser127Tyr) meets criteria to be classified as Pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, PM1, PS3, PS4_Supporting, PP1.

Li-Fraumeni syndrome Pathogenic:1 Uncertain:1

Sep 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 127 of the TP53 protein (p.Ser127Tyr). 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 (internal data). ClinVar contains an entry for this variant (Variation ID: 656751). Invitae Evidence Modeling incorporating data from in vitro 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, 22109999, 29979965). This variant disrupts the p.Ser127 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29470806; internal data). 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.

Aug 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with tyrosine at codon 127 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant is defective in yeast transcriptional transactivation assays and human cell proliferation studies (PMID: 12826609, 29979965), but was inconclusive in human cell growth suppression assays (PMID: 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. The variant has been observed in 10 tumors at cancerhotspots.org. 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.

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 02, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S127Y variant (also known as c.380C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 380. The serine at codon 127 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration has been reported as a somatic mutation 12 times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum. Mutat. 2007 Jun;28:622-9). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.83		Gain of methylation at K132 (P = 0.0696)
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		-0.00020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.87
Mutation Taster		=2/98	disease causing

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: rs730881999; hg19: chr17-7578550; COSMIC: COSV52731113; COSMIC: COSV52731113;