NM_000546.6(TP53):c.480G>A (p.Met160Ile) AND Li-Fraumeni syndrome

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Jan 16, 2025
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000542402.17

Allele description [Variation Report for NM_000546.6(TP53):c.480G>A (p.Met160Ile)]

NM_000546.6(TP53):c.480G>A (p.Met160Ile)

Gene:

TP53:tumor protein p53 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000546.6(TP53):c.480G>A (p.Met160Ile)

Other names:

NM_000546.5(TP53):c.480G>A

HGVS:

NC_000017.11:g.7675132C>T
NG_017013.2:g.17419G>A
NM_000546.6:c.480G>AMANE SELECT
NM_001126112.3:c.480G>A
NM_001126113.3:c.480G>A
NM_001126114.3:c.480G>A
NM_001126115.2:c.84G>A
NM_001126116.2:c.84G>A
NM_001126117.2:c.84G>A
NM_001126118.2:c.363G>A
NM_001276695.3:c.363G>A
NM_001276696.3:c.363G>A
NM_001276697.3:c.3G>A
NM_001276698.3:c.3G>A
NM_001276699.3:c.3G>A
NM_001276760.3:c.363G>A
NM_001276761.3:c.363G>A
NP_000537.3:p.Met160Ile
NP_000537.3:p.Met160Ile
NP_001119584.1:p.Met160Ile
NP_001119585.1:p.Met160Ile
NP_001119586.1:p.Met160Ile
NP_001119587.1:p.Met28Ile
NP_001119588.1:p.Met28Ile
NP_001119589.1:p.Met28Ile
NP_001119590.1:p.Met121Ile
NP_001263624.1:p.Met121Ile
NP_001263625.1:p.Met121Ile
NP_001263626.1:p.Met1Ile
NP_001263627.1:p.Met1Ile
NP_001263628.1:p.Met1Ile
NP_001263689.1:p.Met121Ile
NP_001263690.1:p.Met121Ile
LRG_321t1:c.480G>A
LRG_321:g.17419G>A
LRG_321p1:p.Met160Ile
NC_000017.10:g.7578450C>T
NM_000546.4:c.480G>A
NM_000546.5:c.480G>A
P04637:p.Met160Ile

Protein change:

M121I

Links:

UniProtKB: P04637#VAR_005908; dbSNP: rs772354334

Molecular consequence:

NM_001276697.3:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001276698.3:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001276699.3:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000546.6:c.480G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.480G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.480G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.480G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.84G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.84G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.84G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.363G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.363G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.363G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.363G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.363G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Li-Fraumeni syndrome (LFS)
Synonyms:: Sarcoma family syndrome of Li and Fraumeni
Identifiers:: MONDO: MONDO:0018875; MedGen: C0085390; OMIM: PS151623

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000629827	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 19, 2025)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 29785153, 34284872, 12826609, 29979965, 30224644, 28492532
SCV001949920	ClinGen TP53 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen TP53 ACMG Specifications TP53 V2.0.0)	Likely Benign (Jan 16, 2025)	germline	curation	Citation Link,
SCV004823798	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 30, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 1282660, 29979965, 30224644, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000629827

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 19, 2025)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001949920

ClinGen TP53 Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen TP53 ACMG Specifications TP53 V2.0.0)

Likely Benign
(Jan 16, 2025)

germline

curation

Citation Link,

SCV004823798

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 30, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

Prevalence of deleterious mutations among patients with breast cancer referred for multigene panel testing in a Romanian population.

Goidescu IG, Caracostea G, Eniu DT, Stamatian FV.

Clujul Med. 2018;91(2):157-165. doi: 10.15386/cjmed-894. Epub 2018 Apr 25.

PubMed [citation]

PMID:: 29785153
PMCID:: PMC5958980

Mutational profile of hereditary breast and ovarian cancer - Establishing genetic testing guidelines in a developing country.

Krivokuca A, Mihajlovic M, Susnjar S, Spasojevic IB, Minic I, Popovic L, Brankovic-Magic M.

Curr Probl Cancer. 2022 Feb;46(1):100767. doi: 10.1016/j.currproblcancer.2021.100767. Epub 2021 Jul 10.

PubMed [citation]

PMID:: 34284872

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000629827.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 160 of the TP53 protein (p.Met160Ile). This variant is present in population databases (rs772354334, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 29785153, 34284872). ClinVar contains an entry for this variant (Variation ID: 230758). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) did not meet the statistical confidence thresholds required to predict the impact of this variant on TP53 function. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen TP53 Variant Curation Expert Panel, ClinGen, SCV001949920.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000546.6: c.480G>A variant in TP53 is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 160 (p.Met160Ile). This variant has been observed in 4-7 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_Moderate; Internal lab contributors). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). This variant has an allele frequency of 0.000003390 (4/1180050 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3_Supporting, PM2_Supporting. (Bayesian Points: -2; VCEP specifications version 2.1; 1/16/2025).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004823798.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces methionine with isoleucine at codon 160 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown this variant to have neutral effect on TP53 protein function (PMID: 1282660, 29979965, 30224644). This variant has been reported in an individual affected with breast cancer (PMID 29785153). This variant has been identified in 3/251310 chromosomes 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Apr 12, 2026

ClinVar

Relating variation to medicine