17-7675122-T-C

Variant names:

• chr17-7675122-T-C
• rs879254249
• NM_000546.6:c.490A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PM1_Supporting PS3 PS4_Moderate PP3 PP1 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.490A>G variant in TP53 is a missense variant predicted to cause substitution of lysine by glutamic acid at amino acid 164 (p.Lys164Glu). This variant has been reported in 2 unrelated families meeting Classic/Revised Chompret criteria. Based on this evidence this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMIDs: 33138793, 38050059). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; PMID:38050059). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID:34906512, Internal lab contributors). This variant has an allele frequency of 6.195e-7 (1/1614174 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.5572; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 9 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID:30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PP1, PM2_Supporting, PS3, PP3, PP4, PM1_Supporting. (Bayesian Points: 11; VCEP specifications version 2.3) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584591/MONDO:0018875/009

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: 8.02
• Publications: 91 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.
• PP4: 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.490A>G	p.Lys164Glu	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.490A>G	p.Lys164Glu	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:2

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 164 of the TP53 protein (p.Lys164Glu). 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: 32817165, 33138793, 38050059). ClinVar contains an entry for this variant (Variation ID: 246416). 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, 29979965, 30224644). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jun 05, 2025

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6: c.490A>G variant in TP53 is a missense variant predicted to cause substitution of lysine by glutamic acid at amino acid 164 (p.Lys164Glu). This variant has been reported in 2 unrelated families meeting Classic/Revised Chompret criteria. Based on this evidence this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMIDs: 33138793, 38050059). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; PMID: 38050059). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributors). This variant has an allele frequency of 6.195e-7 (1/1614174 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.5572; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 9 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PP1, PM2_Supporting, PS3, PP3, PP4, PM1_Supporting. (Bayesian Points: 11; VCEP specifications version 2.3) -

Li-Fraumeni syndrome 1 Pathogenic:1 Uncertain:1

Jan 16, 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]. 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: 38050059, 33138793]. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 27, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted TP53 c.490A>G at the cDNA level, p.Lys164Glu (K164E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in multiple tumor types including breast, ovarian, liver, head and neck, and leukemia (Lunn1997, Wang 2004, Pekova 2011, Van der Vorst 2012, Saal 2015). A yeast functional study using a head and neck tumor carrying this variant demonstrated deficient transciptional activity, however this tumor also carried another TP53 variant (Van der Vorst 2012). TP53 Lys164Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Lys164Glu occurs at a position that is conserved across species and is located in the DNA-binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether TP53 Lys164Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D;D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T;T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
PhyloP100		8.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.9	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
Sift4G	Pathogenic	0.0	D;T;T;D;T;T;D;D;T;T;T;T;T;T;T;T;T;T;T;T;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D;.
Vest4		0.91
MutPred		0.79		Loss of MoRF binding (P = 0.0018);Loss of MoRF binding (P = 0.0018);.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0018);.;Loss of MoRF binding (P = 0.0018);Loss of MoRF binding (P = 0.0018);Loss of MoRF binding (P = 0.0018);.;.;Loss of MoRF binding (P = 0.0018);.;.;.;.;Loss of MoRF binding (P = 0.0018);
MVP		1.0
MPC		2.0
ClinPred		0.99	D
GERP RS		4.5
PromoterAI		0.0022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.74

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: rs879254249; hg19: chr17-7578440; COSMIC: COSV52728094; COSMIC: COSV52728094;