NM_000546.6(TP53):c.217G>A (p.Val73Met) AND not specified

Germline classification:: Benign/Likely benign (3 submissions)
Last evaluated:: Feb 6, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001192621.7

Allele description [Variation Report for NM_000546.6(TP53):c.217G>A (p.Val73Met)]

NM_000546.6(TP53):c.217G>A (p.Val73Met)

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.217G>A (p.Val73Met)

HGVS:

NC_000017.11:g.7676152C>T
NG_017013.2:g.16399G>A
NM_000546.6:c.217G>AMANE SELECT
NM_001126112.3:c.217G>A
NM_001126113.3:c.217G>A
NM_001126114.3:c.217G>A
NM_001126118.2:c.100G>A
NM_001276695.3:c.100G>A
NM_001276696.3:c.100G>A
NM_001276760.3:c.100G>A
NM_001276761.3:c.100G>A
NP_000537.3:p.Val73Met
NP_000537.3:p.Val73Met
NP_001119584.1:p.Val73Met
NP_001119585.1:p.Val73Met
NP_001119586.1:p.Val73Met
NP_001119590.1:p.Val34Met
NP_001263624.1:p.Val34Met
NP_001263625.1:p.Val34Met
NP_001263689.1:p.Val34Met
NP_001263690.1:p.Val34Met
LRG_321t1:c.217G>A
LRG_321:g.16399G>A
LRG_321p1:p.Val73Met
NC_000017.10:g.7579470C>T
NM_000546.4:c.217G>A
NM_000546.5(TP53):c.217G>A
NM_000546.5:c.217G>A
P04637:p.Val73Met
p.V73M

Protein change:

V34M

Links:

UniProtKB: P04637#VAR_044607; dbSNP: rs587782423

NCBI 1000 Genomes Browser:

rs587782423

Molecular consequence:

NM_000546.6:c.217G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.217G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.217G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.217G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.100G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.100G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.100G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.100G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.100G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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cytochrome oxidase subunit 1, partial (mitochondrion) [Walckenaeria acuminata]
cytochrome oxidase subunit 1, partial (mitochondrion) [Walckenaeria acuminata]
gi|1488055260|gb|AYG93695.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001360871	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Mar 7, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12826609, 28861920, 30352134, 30840781 Citation Link,
SCV002065423	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jun 28, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004242763	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Feb 6, 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

SCV001360871

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Mar 7, 2021)

germline

clinical testing

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

Citation Link,

SCV002065423

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Jun 28, 2021)

germline

clinical testing

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

SCV004242763

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(Feb 6, 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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history.

de Andrade KC, Mirabello L, Stewart DR, Karlins E, Koster R, Wang M, Gapstur SM, Gaudet MM, Freedman ND, Landi MT, Lemonnier N, Hainaut P, Savage SA, Achatz MI.

Hum Mutat. 2017 Dec;38(12):1723-1730. doi: 10.1002/humu.23320. Epub 2017 Sep 21.

PubMed [citation]

PMID:: 28861920
PMCID:: PMC6858060

See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360871.2

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

Description

Variant summary: TP53 c.217G>A (p.Val73Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250502 control chromosomes. The observed variant frequency is approximately 1.71 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.217G>A in individuals affected with Li-Fraumeni Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Kato_2003, PHANTM database). Four clinical diagnostic laboratories and one expert panel (ClinGen TP53 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=2 to include the expert panel; likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.

#	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 Genetic Services Laboratory, University of Chicago, SCV002065423.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV004242763.1

#	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

Last Updated: Nov 10, 2024

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