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NM_000546.6(TP53):c.220G>T (p.Ala74Ser) AND Li-Fraumeni syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jun 10, 2023
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:
RCV001899847.8

Allele description [Variation Report for NM_000546.6(TP53):c.220G>T (p.Ala74Ser)]

NM_000546.6(TP53):c.220G>T (p.Ala74Ser)

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.220G>T (p.Ala74Ser)
HGVS:
  • NC_000017.11:g.7676149C>A
  • NG_017013.2:g.16402G>T
  • NM_000546.6:c.220G>TMANE SELECT
  • NM_001126112.3:c.220G>T
  • NM_001126113.3:c.220G>T
  • NM_001126114.3:c.220G>T
  • NM_001126118.2:c.103G>T
  • NM_001276695.3:c.103G>T
  • NM_001276696.3:c.103G>T
  • NM_001276760.3:c.103G>T
  • NM_001276761.3:c.103G>T
  • NP_000537.3:p.Ala74Ser
  • NP_001119584.1:p.Ala74Ser
  • NP_001119585.1:p.Ala74Ser
  • NP_001119586.1:p.Ala74Ser
  • NP_001119590.1:p.Ala35Ser
  • NP_001263624.1:p.Ala35Ser
  • NP_001263625.1:p.Ala35Ser
  • NP_001263689.1:p.Ala35Ser
  • NP_001263690.1:p.Ala35Ser
  • LRG_321:g.16402G>T
  • NC_000017.10:g.7579467C>A
Protein change:
A35S
Links:
dbSNP: rs2151041540
NCBI 1000 Genomes Browser:
rs2151041540
Molecular consequence:
  • NM_000546.6:c.220G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.220G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.220G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.220G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.103G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.103G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.103G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.103G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.103G>T - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002122570Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jun 10, 2023) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002122570.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 1361776). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 74 of the TP53 protein (p.Ala74Ser).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024