NM_000546.6(TP53):c.814G>A (p.Val272Met) AND Li-Fraumeni syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Feb 4, 2025
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000457645.15

Allele description [Variation Report for NM_000546.6(TP53):c.814G>A (p.Val272Met)]

NM_000546.6(TP53):c.814G>A (p.Val272Met)

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.814G>A (p.Val272Met)

HGVS:

NC_000017.11:g.7673806C>T
NG_017013.2:g.18745G>A
NM_000546.6:c.814G>AMANE SELECT
NM_001126112.3:c.814G>A
NM_001126113.3:c.814G>A
NM_001126114.3:c.814G>A
NM_001126115.2:c.418G>A
NM_001126116.2:c.418G>A
NM_001126117.2:c.418G>A
NM_001126118.2:c.697G>A
NM_001276695.3:c.697G>A
NM_001276696.3:c.697G>A
NM_001276697.3:c.337G>A
NM_001276698.3:c.337G>A
NM_001276699.3:c.337G>A
NM_001276760.3:c.697G>A
NM_001276761.3:c.697G>A
NP_000537.3:p.Val272Met
NP_000537.3:p.Val272Met
NP_001119584.1:p.Val272Met
NP_001119585.1:p.Val272Met
NP_001119586.1:p.Val272Met
NP_001119587.1:p.Val140Met
NP_001119588.1:p.Val140Met
NP_001119589.1:p.Val140Met
NP_001119590.1:p.Val233Met
NP_001263624.1:p.Val233Met
NP_001263625.1:p.Val233Met
NP_001263626.1:p.Val113Met
NP_001263627.1:p.Val113Met
NP_001263628.1:p.Val113Met
NP_001263689.1:p.Val233Met
NP_001263690.1:p.Val233Met
LRG_321t1:c.814G>A
LRG_321t3:c.814G>A
LRG_321:g.18745G>A
LRG_321p1:p.Val272Met
NC_000017.10:g.7577124C>T
NM_000546.4:c.814G>A
NM_000546.5(TP53):c.814G>A
NM_000546.5:c.814G>A
P04637:p.Val272Met
p.V272M

Protein change:

V113M

Links:

UniProtKB: P04637#VAR_045354; dbSNP: rs121912657

NCBI 1000 Genomes Browser:

rs121912657

Molecular consequence:

NM_000546.6:c.814G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.814G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.814G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.814G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.418G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.418G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.418G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.697G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.697G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.697G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.337G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.337G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.337G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.697G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.697G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000545259	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 25, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 18511570, 23175693, 25584008, 29070607, 29979965, 30224644, 9290701, 9635828, 12826609, 16861262, 22710932, 28492532
SCV004848443	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Aug 10, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005689580	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 4, 2025)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12826609, 30224644, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000545259

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 25, 2024)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV004848443

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Aug 10, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005689580

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 4, 2025)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families.

Bougeard G, Sesboüé R, Baert-Desurmont S, Vasseur S, Martin C, Tinat J, Brugières L, Chompret A, de Paillerets BB, Stoppa-Lyonnet D, Bonaïti-Pellié C, Frébourg T; French LFS working group.

J Med Genet. 2008 Aug;45(8):535-8. doi: 10.1136/jmg.2008.057570. Epub 2008 May 29.

PubMed [citation]

PMID:: 18511570

Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma.

Raymond VM, Else T, Everett JN, Long JM, Gruber SB, Hammer GD.

J Clin Endocrinol Metab. 2013 Jan;98(1):E119-25. doi: 10.1210/jc.2012-2198. Epub 2012 Nov 21.

PubMed [citation]

PMID:: 23175693
PMCID:: PMC3537086

See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000545259.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 272 of the TP53 protein (p.Val272Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 18511570, 23175693, 25584008, 29070607). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 185814). 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: 9290701, 9635828, 12826609, 16861262, 22710932). For these reasons, this variant has been classified as Pathogenic.

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848443.1

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

Description

The p.Val272Met variant in TP53 has been reported in 3 individuals with Li-Fraumeni syndrome or adrenocortical carcinoma and one individual with rhabdomyosarcoma with a de novo mutation (Bougeard 2008 PMID: 18511570, Raymond 2013 PMID: 23175693, Wasserman 2015 PMID: 25584008, Renaux-Petel 2018 PMID: 29070607). It has also been identified in 0.0009% (1/113432) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 185814). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant disrupts the transcriptional transactivation function of the TP53 protein in a temperature sensitive manner (da Costa 2012 PMID: 23165212, Jia 1997 PMID: 9290701, Dearth 2007 PMID: 16861262, Ponchel 1998 PMID: 9635828, Jagosova 2012 PMID: 22710932); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LFS. DISEASE. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting.

#	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 Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, SCV005689580.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

PS3; PM1; PS4_MOD; PM6_Strong

#	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

Last Updated: Mar 29, 2025

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