NM_000546.6(TP53):c.1015G>C (p.Glu339Gln) AND Li-Fraumeni syndrome

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Sep 6, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000697643.13

Allele description [Variation Report for NM_000546.6(TP53):c.1015G>C (p.Glu339Gln)]

NM_000546.6(TP53):c.1015G>C (p.Glu339Gln)

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.1015G>C (p.Glu339Gln)

Other names:

p.E339Q:GAG>CAG; NM_000546.6(TP53):c.1015G>C

HGVS:

NC_000017.11:g.7670694C>G
NG_017013.2:g.21857G>C
NM_000546.6:c.1015G>CMANE SELECT
NM_001126112.3:c.1015G>C
NM_001126113.3:c.*34G>C
NM_001126114.3:c.*122G>C
NM_001126115.2:c.619G>C
NM_001126116.2:c.*122G>C
NM_001126117.2:c.*34G>C
NM_001126118.2:c.898G>C
NM_001276695.3:c.*34G>C
NM_001276696.3:c.*122G>C
NM_001276697.3:c.538G>C
NM_001276698.3:c.*122G>C
NM_001276699.3:c.*34G>C
NM_001276760.3:c.898G>C
NM_001276761.3:c.898G>C
NP_000537.3:p.Glu339Gln
NP_000537.3:p.Glu339Gln
NP_001119584.1:p.Glu339Gln
NP_001119587.1:p.Glu207Gln
NP_001119590.1:p.Glu300Gln
NP_001263626.1:p.Glu180Gln
NP_001263689.1:p.Glu300Gln
NP_001263690.1:p.Glu300Gln
LRG_321t1:c.1015G>C
LRG_321t2:c.1015G>C
LRG_321t6:c.*122G>C
LRG_321:g.21857G>C
LRG_321p1:p.Glu339Gln
NC_000017.10:g.7574012C>G
NM_000546.4:c.1015G>C
NM_000546.5:c.1015G>C
NM_001126112.2(TP53):c.1015G>C
NM_001126116.1:c.*122G>C
P04637:p.Glu339Gln
p.E339Q

Protein change:

E180Q

Links:

UniProtKB: P04637#VAR_045541; dbSNP: rs17882252

NCBI 1000 Genomes Browser:

rs17882252

Molecular consequence:

NM_001126113.3:c.*34G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126114.3:c.*122G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126116.2:c.*122G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126117.2:c.*34G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276695.3:c.*34G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276696.3:c.*122G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276698.3:c.*122G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276699.3:c.*34G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000546.6:c.1015G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.1015G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.619G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.898G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.538G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.898G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.898G>C - 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
SCV000826267	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Oct 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001737935	ClinGen TP53 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen TP53 ACMG Specifications TP53 V2.0.0)	Likely Benign (Sep 6, 2024)	germline	curation	Citation Link,
SCV004823728	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 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

SCV000826267

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Oct 13, 2023)

germline

clinical testing

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

SCV001737935

ClinGen TP53 Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen TP53 ACMG Specifications TP53 V2.0.0)

Likely Benign
(Sep 6, 2024)

germline

curation

Citation Link,

SCV004823728

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 1, 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	3	not provided	not provided	108544	not provided	clinical testing, curation

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 (4)

Details of each submission

From Invitae, SCV000826267.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen TP53 Variant Curation Expert Panel, ClinGen, SCV001737935.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000546.6: c.1015G>C variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by glutamine at amino acid 339 (p.Glu339Gln). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has been observed in 2 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Ambry lab). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, BS3, BP4. (Bayesian Points: -6; VCEP specifications version 2.0; 9/6/2024).

#	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, SCV004823728.1

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

Description

This missense variant replaces glutamic acid with glutamine at codon 339 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 transactivation assays and human cell growth suppression assays (PMID: 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 2/250918 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		3	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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