NM_000546.6(TP53):c.943T>A (p.Ser315Thr) AND Li-Fraumeni syndrome

Clinical significance:Likely benign (Last evaluated: Sep 4, 2020)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000793553.4

Allele description [Variation Report for NM_000546.6(TP53):c.943T>A (p.Ser315Thr)]

NM_000546.6(TP53):c.943T>A (p.Ser315Thr)

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.943T>A (p.Ser315Thr)
HGVS:
  • NC_000017.11:g.7673585A>T
  • NG_017013.2:g.18966T>A
  • NM_000546.5:c.943T>A
  • NM_000546.6:c.943T>AMANE SELECT
  • NM_001126112.3:c.943T>A
  • NM_001126113.3:c.943T>A
  • NM_001126114.3:c.943T>A
  • NM_001126115.2:c.547T>A
  • NM_001126116.2:c.547T>A
  • NM_001126117.2:c.547T>A
  • NM_001126118.2:c.826T>A
  • NM_001276695.3:c.826T>A
  • NM_001276696.3:c.826T>A
  • NM_001276697.3:c.466T>A
  • NM_001276698.3:c.466T>A
  • NM_001276699.3:c.466T>A
  • NM_001276760.3:c.826T>A
  • NM_001276761.3:c.826T>A
  • NP_000537.3:p.Ser315Thr
  • NP_000537.3:p.Ser315Thr
  • NP_001119584.1:p.Ser315Thr
  • NP_001119585.1:p.Ser315Thr
  • NP_001119586.1:p.Ser315Thr
  • NP_001119587.1:p.Ser183Thr
  • NP_001119588.1:p.Ser183Thr
  • NP_001119589.1:p.Ser183Thr
  • NP_001119590.1:p.Ser276Thr
  • NP_001263624.1:p.Ser276Thr
  • NP_001263625.1:p.Ser276Thr
  • NP_001263626.1:p.Ser156Thr
  • NP_001263627.1:p.Ser156Thr
  • NP_001263628.1:p.Ser156Thr
  • NP_001263689.1:p.Ser276Thr
  • NP_001263690.1:p.Ser276Thr
  • LRG_321t1:c.943T>A
  • LRG_321t2:c.943T>A
  • LRG_321:g.18966T>A
  • LRG_321p1:p.Ser315Thr
  • NC_000017.10:g.7576903A>T
  • NM_000546.4:c.943T>A
  • NM_001126112.2(TP53):c.943T>A
  • p.S315T
  • p.Ser315Thr
Protein change:
S156T
Links:
dbSNP: rs762620193
NCBI 1000 Genomes Browser:
rs762620193
Molecular consequence:
  • NM_000546.5:c.943T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000546.6:c.943T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.943T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.943T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.943T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.2:c.547T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.2:c.547T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.2:c.547T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.826T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.826T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.826T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.3:c.466T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.3:c.466T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.3:c.466T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.826T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.826T>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000932911Invitaecriteria provided, single submitter
Uncertain significance
(Oct 7, 2020)
germlineclinical testing

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

SCV001737918ClinGen TP53 Variant Curation Expert Panel,ClinGenreviewed by expert panel
Likely benign
(Sep 4, 2020)
germlinecuration

Citation Link

Summary from all submissions

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

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000932911.3

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

Description

This sequence change replaces serine with threonine at codon 315 of the TP53 protein (p.Ser315Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs762620193, ExAC 0.009%). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 185212). An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). 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.

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

From ClinGen TP53 Variant Curation Expert Panel,ClinGen, SCV001737918.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, TP53 c.943T>A; p.Ser315Thr meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4 and BS3.

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

Last Updated: Nov 27, 2021

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