NM_000546.6(TP53):c.871A>G (p.Lys291Glu) AND Li-Fraumeni syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 13, 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:: RCV000806261.12

Allele description [Variation Report for NM_000546.6(TP53):c.871A>G (p.Lys291Glu)]

NM_000546.6(TP53):c.871A>G (p.Lys291Glu)

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.871A>G (p.Lys291Glu)

HGVS:

NC_000017.11:g.7673749T>C
NG_017013.2:g.18802A>G
NM_000546.6:c.871A>GMANE SELECT
NM_001126112.3:c.871A>G
NM_001126113.3:c.871A>G
NM_001126114.3:c.871A>G
NM_001126115.2:c.475A>G
NM_001126116.2:c.475A>G
NM_001126117.2:c.475A>G
NM_001126118.2:c.754A>G
NM_001276695.3:c.754A>G
NM_001276696.3:c.754A>G
NM_001276697.3:c.394A>G
NM_001276698.3:c.394A>G
NM_001276699.3:c.394A>G
NM_001276760.3:c.754A>G
NM_001276761.3:c.754A>G
NP_000537.3:p.Lys291Glu
NP_000537.3:p.Lys291Glu
NP_001119584.1:p.Lys291Glu
NP_001119585.1:p.Lys291Glu
NP_001119586.1:p.Lys291Glu
NP_001119587.1:p.Lys159Glu
NP_001119588.1:p.Lys159Glu
NP_001119589.1:p.Lys159Glu
NP_001119590.1:p.Lys252Glu
NP_001263624.1:p.Lys252Glu
NP_001263625.1:p.Lys252Glu
NP_001263626.1:p.Lys132Glu
NP_001263627.1:p.Lys132Glu
NP_001263628.1:p.Lys132Glu
NP_001263689.1:p.Lys252Glu
NP_001263690.1:p.Lys252Glu
LRG_321t1:c.871A>G
LRG_321:g.18802A>G
LRG_321p1:p.Lys291Glu
NC_000017.10:g.7577067T>C
NM_000546.4:c.871A>G
NM_000546.5:c.871A>G

Protein change:

K132E

Links:

dbSNP: rs1555525126

NCBI 1000 Genomes Browser:

rs1555525126

Molecular consequence:

NM_000546.6:c.871A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.871A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.871A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.871A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.394A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.394A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.394A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.754A>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
SCV000946250	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 13, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 29979965, 30224644, 12826609, 15781620, 28492532
SCV004843732	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 20, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12826609, 15781620, 29979965, 30224644, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000946250

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 13, 2023)

germline

clinical testing

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

SCV004843732

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 20, 2023)

germline

clinical testing

PubMed (5)
[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

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

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

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000946250.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 291 of the TP53 protein (p.Lys291Glu). This variant is not present in population databases (gnomAD no frequency). 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: 480951). 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, 15781620). 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, SCV004843732.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces lysine with glutamic acid at codon 291 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant is functional in yeast transcriptional transactivation, human cell growth suprression and proliferation, and apoptosis induction assays (PMID: 15781620, 12826609, 29979965, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified 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: Sep 29, 2024

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