NM_000546.6(TP53):c.31G>A (p.Glu11Lys) AND Li-Fraumeni syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 13, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000548671.18

Allele description [Variation Report for NM_000546.6(TP53):c.31G>A (p.Glu11Lys)]

NM_000546.6(TP53):c.31G>A (p.Glu11Lys)

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.31G>A (p.Glu11Lys)

HGVS:

NC_000017.11:g.7676564C>T
NG_017013.2:g.15987G>A
NM_000546.6:c.31G>AMANE SELECT
NM_001126112.3:c.31G>A
NM_001126113.3:c.31G>A
NM_001126114.3:c.31G>A
NM_001126118.2:c.-204G>A
NM_001276695.3:c.-87G>A
NM_001276696.3:c.-87G>A
NM_001276760.3:c.-87G>A
NM_001276761.3:c.-87G>A
NP_000537.3:p.Glu11Lys
NP_000537.3:p.Glu11Lys
NP_001119584.1:p.Glu11Lys
NP_001119585.1:p.Glu11Lys
NP_001119586.1:p.Glu11Lys
LRG_321t1:c.31G>A
LRG_321:g.15987G>A
LRG_321p1:p.Glu11Lys
NC_000017.10:g.7579882C>T
NM_000546.4:c.31G>A
NM_000546.5:c.31G>A

Protein change:

E11K

Links:

dbSNP: rs201382018

NCBI 1000 Genomes Browser:

rs201382018

Molecular consequence:

NM_001126118.2:c.-204G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276695.3:c.-87G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276696.3:c.-87G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276760.3:c.-87G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276761.3:c.-87G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.31G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.31G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.31G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.31G>A - 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
SCV000629802	Invitae	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, 9207066, 12826609, 30224644, 28492532
SCV004823863	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Benign (Oct 30, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000629802

Invitae

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]

SCV004823863

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Benign
(Oct 30, 2023)

germline

clinical testing

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

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

Interaction between replication protein A and p53 is disrupted after UV damage in a DNA repair-dependent manner.

Abramova NA, Russell J, Botchan M, Li R.

Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7186-91.

PubMed [citation]

PMID:: 9207066
PMCID:: PMC23787

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000629802.8

#	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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 11 of the TP53 protein (p.Glu11Lys). This variant is present in population databases (rs201382018, gnomAD 0.004%). 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: 418693). 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: 9207066, 12826609, 30224644). 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, SCV004823863.1

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

#	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: Jul 29, 2024

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