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NM_000546.6(TP53):c.188C>G (p.Ala63Gly) AND Li-Fraumeni syndrome

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Oct 23, 2023
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:
RCV000465288.13

Allele description [Variation Report for NM_000546.6(TP53):c.188C>G (p.Ala63Gly)]

NM_000546.6(TP53):c.188C>G (p.Ala63Gly)

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.188C>G (p.Ala63Gly)
Other names:
NM_000546.6(TP53):c.188C>G
HGVS:
  • NC_000017.11:g.7676181G>C
  • NG_017013.2:g.16370C>G
  • NM_000546.6:c.188C>GMANE SELECT
  • NM_001126112.3:c.188C>G
  • NM_001126113.3:c.188C>G
  • NM_001126114.3:c.188C>G
  • NM_001126118.2:c.71C>G
  • NM_001276695.3:c.71C>G
  • NM_001276696.3:c.71C>G
  • NM_001276760.3:c.71C>G
  • NM_001276761.3:c.71C>G
  • NP_000537.3:p.Ala63Gly
  • NP_000537.3:p.Ala63Gly
  • NP_001119584.1:p.Ala63Gly
  • NP_001119585.1:p.Ala63Gly
  • NP_001119586.1:p.Ala63Gly
  • NP_001119590.1:p.Ala24Gly
  • NP_001263624.1:p.Ala24Gly
  • NP_001263625.1:p.Ala24Gly
  • NP_001263689.1:p.Ala24Gly
  • NP_001263690.1:p.Ala24Gly
  • LRG_321t1:c.188C>G
  • LRG_321:g.16370C>G
  • LRG_321p1:p.Ala63Gly
  • NC_000017.10:g.7579499G>C
  • NM_000546.4:c.188C>G
  • NM_000546.5:c.188C>G
Protein change:
A24G
Links:
dbSNP: rs372201428
NCBI 1000 Genomes Browser:
rs372201428
Molecular consequence:
  • NM_000546.6:c.188C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.188C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.188C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.188C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.71C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.71C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.71C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.71C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.71C>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV000545280Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Oct 23, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004823840All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Oct 2, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children.

Qian M, Cao X, Devidas M, Yang W, Cheng C, Dai Y, Carroll A, Heerema NA, Zhang H, Moriyama T, Gastier-Foster JM, Xu H, Raetz E, Larsen E, Winick N, Bowman WP, Martin PL, Mardis ER, Fulton R, Zambetti G, Borowitz M, Wood B, et al.

J Clin Oncol. 2018 Feb 20;36(6):591-599. doi: 10.1200/JCO.2017.75.5215. Epub 2018 Jan 4.

PubMed [citation]
PMID:
29300620
PMCID:
PMC5815403

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

Kotler E, Shani O, Goldfeld G, Lotan-Pompan M, Tarcic O, Gershoni A, Hopf TA, Marks DS, Oren M, Segal E.

Mol Cell. 2018 Jul 5;71(1):178-190.e8. doi: 10.1016/j.molcel.2018.06.012. Erratum in: Mol Cell. 2018 Sep 6;71(5):873. doi: 10.1016/j.molcel.2018.08.013.

PubMed [citation]
PMID:
29979965
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000545280.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 63 of the TP53 protein (p.Ala63Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute lymphocytic leukemia (PMID: 29300620). ClinVar contains an entry for this variant (Variation ID: 229693). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 All of Us Research Program, National Institutes of Health, SCV004823840.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)

Description

This variant is located in the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant behaves like wild-type in yeast transactivation studies and human cell growth suppression assays (PMID: 11359905, 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has been identified in 1/31376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024