NM_000546.6(TP53):c.233C>G (p.Ala78Gly) AND Li-Fraumeni syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 30, 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:: RCV000552207.10

Allele description [Variation Report for NM_000546.6(TP53):c.233C>G (p.Ala78Gly)]

NM_000546.6(TP53):c.233C>G (p.Ala78Gly)

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.233C>G (p.Ala78Gly)

HGVS:

NC_000017.11:g.7676136G>C
NG_017013.2:g.16415C>G
NM_000546.6:c.233C>GMANE SELECT
NM_001126112.3:c.233C>G
NM_001126113.3:c.233C>G
NM_001126114.3:c.233C>G
NM_001126118.2:c.116C>G
NM_001276695.3:c.116C>G
NM_001276696.3:c.116C>G
NM_001276760.3:c.116C>G
NM_001276761.3:c.116C>G
NP_000537.3:p.Ala78Gly
NP_000537.3:p.Ala78Gly
NP_001119584.1:p.Ala78Gly
NP_001119585.1:p.Ala78Gly
NP_001119586.1:p.Ala78Gly
NP_001119590.1:p.Ala39Gly
NP_001263624.1:p.Ala39Gly
NP_001263625.1:p.Ala39Gly
NP_001263689.1:p.Ala39Gly
NP_001263690.1:p.Ala39Gly
LRG_321t1:c.233C>G
LRG_321:g.16415C>G
LRG_321p1:p.Ala78Gly
NC_000017.10:g.7579454G>C
NM_000546.4:c.233C>G
NM_000546.5:c.233C>G

Protein change:

A39G

Links:

dbSNP: rs876658527

NCBI 1000 Genomes Browser:

rs876658527

Molecular consequence:

NM_000546.6:c.233C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.233C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.233C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.233C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.116C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.116C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.116C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.116C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.116C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000629794	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 29, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12826609, 29979965, 30224644, 28492532
SCV004823829	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 30, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12826609, 30224644, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000629794

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 29, 2023)

germline

clinical testing

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

SCV004823829

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 30, 2023)

germline

clinical testing

PubMed (3)
[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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

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

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

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000629794.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 78 of the TP53 protein (p.Ala78Gly). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 230368). 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%. 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.

#	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

From All of Us Research Program, National Institutes of Health, SCV004823829.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces alanine with glycine at codon 78 of 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 reported the mutant protein to be functional in yeast transactivation assays (IARC database and PMID: 12826609) and in human cell growth suppression assays (PMID: 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250492 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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