NM_000546.6(TP53):c.21T>A (p.Asp7Glu) AND Li-Fraumeni syndrome

Germline classification:: Likely 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:: RCV000802467.9

Allele description [Variation Report for NM_000546.6(TP53):c.21T>A (p.Asp7Glu)]

NM_000546.6(TP53):c.21T>A (p.Asp7Glu)

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.21T>A (p.Asp7Glu)

Other names:

p.D7E:GAT>GAA; NM_000546.6(TP53):c.21T>A

HGVS:

NC_000017.11:g.7676574A>T
NG_017013.2:g.15977T>A
NM_000546.6:c.21T>AMANE SELECT
NM_001126112.3:c.21T>A
NM_001126113.3:c.21T>A
NM_001126114.3:c.21T>A
NM_001126118.2:c.-214T>A
NM_001276695.3:c.-97T>A
NM_001276696.3:c.-97T>A
NM_001276760.3:c.-97T>A
NM_001276761.3:c.-97T>A
NP_000537.3:p.Asp7Glu
NP_000537.3:p.Asp7Glu
NP_001119584.1:p.Asp7Glu
NP_001119585.1:p.Asp7Glu
NP_001119586.1:p.Asp7Glu
LRG_321t1:c.21T>A
LRG_321:g.15977T>A
LRG_321p1:p.Asp7Glu
NC_000017.10:g.7579892A>T
NC_000017.10:g.7579892A>T
NM_000546.4:c.21T>A
NM_000546.5(TP53):c.21T>A
NM_000546.5:c.21T>A
p.Asp7Glu
p.D7E

Protein change:

D7E

Links:

dbSNP: rs587781277

NCBI 1000 Genomes Browser:

rs587781277

Molecular consequence:

NM_001126118.2:c.-214T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276695.3:c.-97T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276696.3:c.-97T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276760.3:c.-97T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276761.3:c.-97T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.21T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.21T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.21T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.21T>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

Recent activity

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phosphatidylinositol glycan, class F, isoform CRA_f [Homo sapiens]
phosphatidylinositol glycan, class F, isoform CRA_f [Homo sapiens]
gi|119620650|gb|EAX00245.1||gnl|WGS |hCP1815788

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000942300	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29979965, 12826609, 30224644, 28492532
SCV001142536	ClinGen TP53 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen TP53 ACMG Specifications TP53 V2.0.0)	Likely Benign (Aug 5, 2024)	germline	curation	Citation Link,
SCV004823867	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (May 4, 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

SCV000942300

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 13, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001142536

ClinGen TP53 Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen TP53 ACMG Specifications TP53 V2.0.0)

Likely Benign
(Aug 5, 2024)

germline

curation

Citation Link,

SCV004823867

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(May 4, 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	1	not provided	not provided	108544	not provided	clinical testing, curation

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

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

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000942300.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 7 of the TP53 protein (p.Asp7Glu). 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: 140782). 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, 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, SCV001142536.2

#	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.21T>A variant in TP53 is a missense variant predicted to cause substitution of Aspartic acid by Glutamic acid at amino acid 7 (p.Asp7Glu). 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 = -0.0153; 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). This variant has an allele frequency of 0.000001859 (3/1613882 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). 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: BS3, BP4_moderate, PM2_Supporting (Bayesian Points: -5; 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, SCV004823867.1

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

Description

This missense variant replaces aspartic acid with glutamic acid at codon 7 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 the mutant protein to be functional in yeast transactivation assay (PMID: 12826609 and IARC database) and to lack a dominant negative effect or loss-of-function phenotype in human cell growth assay (PMID: 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer 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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