NM_000546.6(TP53):c.892G>A (p.Glu298Lys) AND Li-Fraumeni syndrome

Germline classification:: Benign (3 submissions)
Last evaluated:: Aug 5, 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:: RCV000206802.20

Allele description [Variation Report for NM_000546.6(TP53):c.892G>A (p.Glu298Lys)]

NM_000546.6(TP53):c.892G>A (p.Glu298Lys)

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.892G>A (p.Glu298Lys)

HGVS:

NC_000017.11:g.7673728C>T
NG_017013.2:g.18823G>A
NM_000546.6:c.892G>AMANE SELECT
NM_001126112.3:c.892G>A
NM_001126113.3:c.892G>A
NM_001126114.3:c.892G>A
NM_001126115.2:c.496G>A
NM_001126116.2:c.496G>A
NM_001126117.2:c.496G>A
NM_001126118.2:c.775G>A
NM_001276695.3:c.775G>A
NM_001276696.3:c.775G>A
NM_001276697.3:c.415G>A
NM_001276698.3:c.415G>A
NM_001276699.3:c.415G>A
NM_001276760.3:c.775G>A
NM_001276761.3:c.775G>A
NP_000537.3:p.Glu298Lys
NP_000537.3:p.Glu298Lys
NP_001119584.1:p.Glu298Lys
NP_001119585.1:p.Glu298Lys
NP_001119586.1:p.Glu298Lys
NP_001119587.1:p.Glu166Lys
NP_001119588.1:p.Glu166Lys
NP_001119589.1:p.Glu166Lys
NP_001119590.1:p.Glu259Lys
NP_001263624.1:p.Glu259Lys
NP_001263625.1:p.Glu259Lys
NP_001263626.1:p.Glu139Lys
NP_001263627.1:p.Glu139Lys
NP_001263628.1:p.Glu139Lys
NP_001263689.1:p.Glu259Lys
NP_001263690.1:p.Glu259Lys
LRG_321t1:c.892G>A
LRG_321:g.18823G>A
LRG_321p1:p.Glu298Lys
NC_000017.10:g.7577046C>T
NM_000546.4:c.892G>A
NM_000546.5(TP53):c.892G>A
NM_000546.5:c.892G>A
P04637:p.Glu298Lys
p.E298K

Protein change:

E139K

Links:

UniProtKB: P04637#VAR_045448; dbSNP: rs201744589

NCBI 1000 Genomes Browser:

rs201744589

Molecular consequence:

NM_000546.6:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.496G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.496G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.496G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.775G>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
SCV000260657	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001142530	ClinGen TP53 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen TP53 ACMG Specifications TP53 V2.0.0)	Benign (Aug 5, 2024)	germline	curation	Citation Link,
SCV004823752	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12826609, 21747090, 30224644, 31949278, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000260657

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Jan 26, 2024)

germline

clinical testing

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

SCV001142530

ClinGen TP53 Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen TP53 ACMG Specifications TP53 V2.0.0)

Benign
(Aug 5, 2024)

germline

curation

Citation Link,

SCV004823752

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

germline

clinical testing

PubMed (6)
[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	5	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 (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000260657.12

#	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, SCV001142530.2

#	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.892G>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 298 (p.Gly298Lys). This variant has been observed in 4-7 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_Moderate; SCV000184859, SCV000260657). 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). Computational predictor scores (BayesDel = -0.199; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3, BP4_Moderate. (Bayesian Points: -8; VCEP specifications version 2.0; 7/24/2024)

#	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, SCV004823752.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces glutamic acid with lysine at codon 298 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). Experimental studies have shown this variant to be functional in transcriptional transactivation and cell growth suppression assays (PMID: 12826609, 30224644). This variant has been reported in individuals affected with gastric cancer and acute lymphocytic leukemia in the literature (PMID: 21747090, 31949278). In a large international case-control study, this variant was reported in 1/60465 cases breast cancer cases and 2/53459 controls (OR=0.442, 95%CI 0.04 to 4.876, p-value=0.603; PMID: 33471991). This variant has been identified in 3/251492 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		5	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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