NM_000546.6(TP53):c.145G>A (p.Asp49Asn) 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:: RCV000540357.17

Allele description [Variation Report for NM_000546.6(TP53):c.145G>A (p.Asp49Asn)]

NM_000546.6(TP53):c.145G>A (p.Asp49Asn)

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.145G>A (p.Asp49Asn)

HGVS:

NC_000017.11:g.7676224C>T
NG_017013.2:g.16327G>A
NM_000546.6:c.145G>AMANE SELECT
NM_001126112.3:c.145G>A
NM_001126113.3:c.145G>A
NM_001126114.3:c.145G>A
NM_001126118.2:c.28G>A
NM_001276695.3:c.28G>A
NM_001276696.3:c.28G>A
NM_001276760.3:c.28G>A
NM_001276761.3:c.28G>A
NP_000537.3:p.Asp49Asn
NP_000537.3:p.Asp49Asn
NP_001119584.1:p.Asp49Asn
NP_001119585.1:p.Asp49Asn
NP_001119586.1:p.Asp49Asn
NP_001119590.1:p.Asp10Asn
NP_001263624.1:p.Asp10Asn
NP_001263625.1:p.Asp10Asn
NP_001263689.1:p.Asp10Asn
NP_001263690.1:p.Asp10Asn
LRG_321t1:c.145G>A
LRG_321:g.16327G>A
LRG_321p1:p.Asp49Asn
NC_000017.10:g.7579542C>T
NM_000546.4:c.145G>A
NM_000546.5(TP53):c.145G>A
NM_000546.5:c.145G>A
P04637:p.Asp49Asn
p.D49N

Protein change:

D10N

Links:

UniProtKB: P04637#VAR_044572; dbSNP: rs587780728

NCBI 1000 Genomes Browser:

rs587780728

Molecular consequence:

NM_000546.6:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.28G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.28G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.28G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.28G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.28G>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
SCV000629784	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2025)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26554828, 29979965, 12826609, 30224644, 28492532
SCV001142537	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,
SCV004823846	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Benign (Feb 5, 2024)	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

SCV000629784

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 29, 2025)

germline

clinical testing

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

SCV001142537

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,

SCV004823846

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Benign
(Feb 5, 2024)

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	3	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

Gender-Specific Molecular and Clinical Features Underlie Malignant Pleural Mesothelioma.

De Rienzo A, Archer MA, Yeap BY, Dao N, Sciaranghella D, Sideris AC, Zheng Y, Holman AG, Wang YE, Dal Cin PS, Fletcher JA, Rubio R, Croft L, Quackenbush J, Sugarbaker PE, Munir KJ, Battilana JR, Gustafson CE, Chirieac LR, Ching SM, Wong J, Tay LC, et al.

Cancer Res. 2016 Jan 15;76(2):319-28. doi: 10.1158/0008-5472.CAN-15-0751. Epub 2015 Nov 10.

PubMed [citation]

PMID:: 26554828
PMCID:: PMC4715909

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

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000629784.10

#	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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 49 of the TP53 protein (p.Asp49Asn). This variant is present in population databases (rs587780728, gnomAD 0.01%). This missense change has been observed in individual(s) with mesothelioma and skin cancer (PMID: 26554828). ClinVar contains an entry for this variant (Variation ID: 186363). Invitae Evidence Modeling incorporating data from in vitro 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, 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 ClinGen TP53 Variant Curation Expert Panel, ClinGen, SCV001142537.2

#	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.145G>A variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 49 (p.Asp49Asn). This variant has been observed in at least 8 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; ClinVar SCV: SCV000216702.6). This variant has an allele frequency of 0.0000111525 (18/1613988 alleles) across gnomAD v4.1.0 (after removing low AB alleles likely to represent CHIP contamination and recalculating total allele frequency) which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). 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 = -0.232; Align GVGD Class C0) 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, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -9; 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, SCV004823846.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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		3	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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