NM_000546.6(TP53):c.841G>C (p.Asp281His) AND Li-Fraumeni syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 22, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001306199.10

Allele description [Variation Report for NM_000546.6(TP53):c.841G>C (p.Asp281His)]

NM_000546.6(TP53):c.841G>C (p.Asp281His)

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.841G>C (p.Asp281His)

HGVS:

NC_000017.11:g.7673779C>G
NG_017013.2:g.18772G>C
NM_000546.6:c.841G>CMANE SELECT
NM_001126112.3:c.841G>C
NM_001126113.3:c.841G>C
NM_001126114.3:c.841G>C
NM_001126115.2:c.445G>C
NM_001126116.2:c.445G>C
NM_001126117.2:c.445G>C
NM_001126118.2:c.724G>C
NM_001276695.3:c.724G>C
NM_001276696.3:c.724G>C
NM_001276697.3:c.364G>C
NM_001276698.3:c.364G>C
NM_001276699.3:c.364G>C
NM_001276760.3:c.724G>C
NM_001276761.3:c.724G>C
NP_000537.3:p.Asp281His
NP_001119584.1:p.Asp281His
NP_001119585.1:p.Asp281His
NP_001119586.1:p.Asp281His
NP_001119587.1:p.Asp149His
NP_001119588.1:p.Asp149His
NP_001119589.1:p.Asp149His
NP_001119590.1:p.Asp242His
NP_001263624.1:p.Asp242His
NP_001263625.1:p.Asp242His
NP_001263626.1:p.Asp122His
NP_001263627.1:p.Asp122His
NP_001263628.1:p.Asp122His
NP_001263689.1:p.Asp242His
NP_001263690.1:p.Asp242His
LRG_321:g.18772G>C
NC_000017.10:g.7577097C>G
NM_000546.4:c.841G>C

Protein change:

D122H

Links:

dbSNP: rs764146326

Molecular consequence:

NM_000546.6:c.841G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.841G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.841G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.841G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.445G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.445G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.445G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.724G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.724G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.724G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.364G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.364G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.364G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.724G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.724G>C - 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
SCV001495560	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 22, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 34240179, 12826609, 29979965, 30224644, 15925506, 17390010, 17572079, 21305319, 23894400, 25293557, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001495560

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 22, 2024)

germline

clinical testing

PubMed (11)
[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

Paired Tumor-Normal Sequencing Provides Insights Into the TP53-Related Cancer Spectrum in Patients With Li-Fraumeni Syndrome.

Ceyhan-Birsoy O, Selenica P, Chui MH, Jayakumaran G, Ptashkin R, Misyura M, Aypar U, Jairam S, Yang C, Li Y, Mehta N, Kemel Y, Salo-Mullen E, Maio A, Sheehan M, Zehir A, Carlo M, Latham A, Stadler Z, Robson M, Offit K, Ladanyi M, et al.

J Natl Cancer Inst. 2021 Nov 29;113(12):1751-1760. doi: 10.1093/jnci/djab117.

PubMed [citation]

PMID:: 34240179
PMCID:: PMC9891110

Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.

Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C.

Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9. Epub 2003 Jun 25.

PubMed [citation]

PMID:: 12826609
PMCID:: PMC166245

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001495560.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 281 of the TP53 protein (p.Asp281His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical history consistent with Li-Fraumeni syndrome and/or Li-Fraumeni syndrome (PMID: 34240179; Invitae). ClinVar contains an entry for this variant (Variation ID: 376588). 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, 29979965, 30224644). This variant disrupts the p.Asp281 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15925506, 17390010, 17572079, 21305319, 23894400, 25293557). 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.

#	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: Apr 12, 2026

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