NM_000546.6(TP53):c.747G>T AND Li-Fraumeni syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: May 25, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000464372.2

Allele description [Variation Report for NM_000546.6(TP53):c.747G>T]

NM_000546.6(TP53):c.747G>T

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.747G>T
HGVS:
  • NC_000017.11:g.7674216C>A
  • NG_017013.2:g.18335G>T
  • NM_000546.5:c.747G>T
  • NM_000546.6:c.747G>TMANE SELECT
  • NM_001126112.2:c.747G>T
  • NM_001126113.2:c.747G>T
  • NM_001126114.2:c.747G>T
  • NM_001126115.1:c.351G>T
  • NM_001126116.1:c.351G>T
  • NM_001126117.1:c.351G>T
  • NM_001126118.1:c.630G>T
  • NM_001276695.2:c.630G>T
  • NM_001276696.2:c.630G>T
  • NM_001276697.2:c.270G>T
  • NM_001276698.2:c.270G>T
  • NM_001276699.2:c.270G>T
  • NM_001276760.2:c.630G>T
  • NM_001276761.2:c.630G>T
  • NP_000537.3:p.Arg249Ser
  • NP_001119584.1:p.Arg249Ser
  • NP_001119585.1:p.Arg249Ser
  • NP_001119586.1:p.Arg249Ser
  • NP_001119587.1:p.Arg117Ser
  • NP_001119588.1:p.Arg117Ser
  • NP_001119589.1:p.Arg117Ser
  • NP_001119590.1:p.Arg210Ser
  • NP_001263624.1:p.Arg210Ser
  • NP_001263625.1:p.Arg210Ser
  • NP_001263626.1:p.Arg90Ser
  • NP_001263627.1:p.Arg90Ser
  • NP_001263628.1:p.Arg90Ser
  • NP_001263689.1:p.Arg210Ser
  • NP_001263690.1:p.Arg210Ser
  • LRG_321t1:c.747G>T
  • LRG_321t2:c.747G>T
  • LRG_321t3:c.747G>T
  • LRG_321t4:c.747G>T
  • LRG_321t5:c.351G>T
  • LRG_321t6:c.351G>T
  • LRG_321t7:c.351G>T
  • LRG_321t8:c.630G>T
  • LRG_321:g.18335G>T
  • LRG_321:p.Arg249Ser
  • LRG_321p1:p.Arg249Ser
  • LRG_321p3:p.Arg249Ser
  • LRG_321p4:p.Arg249Ser
  • LRG_321p5:p.Arg117Ser
  • LRG_321p6:p.Arg117Ser
  • LRG_321p7:p.Arg117Ser
  • LRG_321p8:p.Arg210Ser
  • NC_000017.10:g.7577534C>A
  • NM_000546.4:c.747G>T
  • P04637:p.Arg249Ser
Protein change:
R117S; ARG249SER
Links:
UniProtKB: P04637#VAR_005986; OMIM: 191170.0006; dbSNP: rs28934571
NCBI 1000 Genomes Browser:
rs28934571
Molecular consequence:
  • NM_000546.5:c.747G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.2:c.747G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.2:c.747G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.2:c.747G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.1:c.351G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.1:c.351G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.1:c.351G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.1:c.630G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.2:c.630G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.2:c.630G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.2:c.270G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.2:c.270G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.2:c.270G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.2:c.630G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.2:c.630G>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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000545320Invitaecriteria provided, single submitter
Uncertain significance
(Aug 10, 2016)
germlineclinical testing

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

SCV000886463University of Washington Department of Laboratory Medicine, University of Washingtoncriteria provided, single submitter
Pathogenic
(May 25, 2018)
germlineresearch

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot provided1not providednot providedyesresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.

Tsai GJ, Rañola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, Bowen DJ, Shirts BH.

Genet Med. 2019 Jun;21(6):1435-1442. doi: 10.1038/s41436-018-0335-7. Epub 2018 Oct 30.

PubMed [citation]
PMID:
30374176

Details of each submission

From Invitae, SCV000545320.2

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

Description

This sequence change replaces arginine with serine at codon 249 of the TP53 protein (p.Arg249Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease. However, this variant has been identified as a hot spot in hepatocellular carcinoma and is the 7th most frequent single codon TP53 mutation found in human cancer biopsies (PMID: 1849234, 19756158, 20538734, 15095302, 17311302). ClinVar contains an entry for this variant (Variation ID: 12352). Experimental studies have shown that this missense change affects TP53 protein structure and disrupts protein function (PMID: 15703170, 15982667, 9405613, 12826609, 20538734, 15060172, 18477611). In summary, this variant is a rare missense change that disrupts protein function. While it is absent from the population and reported in many cancer cell biopsies, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000886463.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providedyesresearch PubMed (1)

Description

The TP53 variant designated as NM_000546.5:c.747G>T (p.Arg249Ser) is classified as pathogenic. This variant has not been reported in public population databases. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 7.52 to 1 that this allele explains cancer in the family (Thompson et al, 2003, PMID:2900794). Computer software programs (SIFT, Polyphen-2, PROVEAN) predict that this variant is likely to have a damaging effect. Experimental functional studies provide evidence that this variant can lead to loss of function by disrupting protein structure (Gouas et al, 2010, PMID: 20538734; Lee et al, 2008, PMID: 18477611; Butler et al, 2005, PMID: 15982667; Joerger et al, 2005, PMID: 15703170; Chan et al, 2004, PMID:15060172; Kato et al, 2003, PMID: 12826609; Bullock et al, 1997, PMID: 9405613). Additionally, analysis of breast tumor in one member of the observed family shows loss of heterozygosity for the allele with this TP53 variant in breast tissue, which adds moderate evidence that this variant is pathogenic. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 99% probability of pathogenicity, which is consistent with a classification of pathogenic. The combined results are consistent with a classification of pathogenic in the context of Li-Fraumeni syndrome. This variant is expected to alter TP53 function and increase risks related to Li-Fraumeni syndrome associated cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot provided1not provided

Last Updated: Aug 17, 2021

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