NM_000546.6(TP53):c.869G>A (p.Arg290His) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Aug 15, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000213061.21

Allele description [Variation Report for NM_000546.6(TP53):c.869G>A (p.Arg290His)]

NM_000546.6(TP53):c.869G>A (p.Arg290His)

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.869G>A (p.Arg290His)

Other names:

p.R290H:CGC>CAC

HGVS:

NC_000017.11:g.7673751C>T
NG_017013.2:g.18800G>A
NM_000546.6:c.869G>AMANE SELECT
NM_001126112.3:c.869G>A
NM_001126113.3:c.869G>A
NM_001126114.3:c.869G>A
NM_001126115.1:c.473G>A
NM_001126115.2:c.473G>A
NM_001126116.2:c.473G>A
NM_001126117.2:c.473G>A
NM_001126118.2:c.752G>A
NM_001276695.3:c.752G>A
NM_001276696.3:c.752G>A
NM_001276697.3:c.392G>A
NM_001276698.3:c.392G>A
NM_001276699.3:c.392G>A
NM_001276760.3:c.752G>A
NM_001276761.3:c.752G>A
NP_000537.3:p.Arg290His
NP_000537.3:p.Arg290His
NP_001119584.1:p.Arg290His
NP_001119585.1:p.Arg290His
NP_001119586.1:p.Arg290His
NP_001119587.1:p.Arg158His
NP_001119588.1:p.Arg158His
NP_001119589.1:p.Arg158His
NP_001119590.1:p.Arg251His
NP_001263624.1:p.Arg251His
NP_001263625.1:p.Arg251His
NP_001263626.1:p.Arg131His
NP_001263627.1:p.Arg131His
NP_001263628.1:p.Arg131His
NP_001263689.1:p.Arg251His
NP_001263690.1:p.Arg251His
LRG_321t1:c.869G>A
LRG_321:g.18800G>A
LRG_321p1:p.Arg290His
NC_000017.10:g.7577069C>T
NM_000546.4:c.869G>A
NM_000546.5(TP53):c.869G>A
NM_000546.5:c.869G>A
P04637:p.Arg290His
p.R290H

Protein change:

R131H

Links:

UniProtKB: P04637#VAR_045411; dbSNP: rs55819519

NCBI 1000 Genomes Browser:

rs55819519

Molecular consequence:

NM_000546.6:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.752G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.752G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.752G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.752G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.752G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000540572	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 25, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000920323	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (May 23, 2022)	germline	clinical testing	PubMed (29) [See all records that cite these PMIDs] 22811390, 25925845, 10922393, 17606709, 21343334, 20407015, 28135145, 26230955, 21519010, 27463065, 25952993, 22186996, 27680515, 27959731, 16818505, 28369373, 27895058, 30327374, 29365323, 19468865, 11782540, 23246812, 22915647, 26585234, 29300620, 27276561, 10435620, 29979965, 33300245 Citation Link,
SCV002550936	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Aug 15, 2023)	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

SCV000540572

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 25, 2017)

germline

clinical testing

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

SCV000920323

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(May 23, 2022)

germline

clinical testing

PubMed (29)
[See all records that cite these PMIDs]

Citation Link,

SCV002550936

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(Aug 15, 2023)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma.

Pennington KP, Walsh T, Lee M, Pennil C, Novetsky AP, Agnew KJ, Thornton A, Garcia R, Mutch D, King MC, Goodfellow P, Swisher EM.

Cancer. 2013 Jan 15;119(2):332-8. doi: 10.1002/cncr.27720. Epub 2012 Jul 18.

PubMed [citation]

PMID:: 22811390
PMCID:: PMC3966566

See all PubMed Citations (31)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000540572.1

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

Description

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 8 papers, including at least 3 individuals with Li-Fraumeni syndrome as well as individuals with other cancers. The variant has a Max MAF of 0.02% in ExAC (16 alleles) and 0.03% in gnomAD (9 Finnish alleles and 26 non-Finnish European alleles). It is classified with 1 star in ClinVar as VUS by Invitae, Ambry, GeneDx and CSER_CC_NCGL, and as Pathogenic by UCLA. 14 mammals and 2 non-mammals have a His at this position.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000920323.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (29)

Description

Variant summary: TP53 c.869G>A (p.Arg290His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251482 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00021 in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency (MPAF) for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05). In addition, the variant was reported to be found in the FLOSSIES database in 7/9884 women, who were older than age 70 years and have never had cancer. The frequency in this cohort (0.000354) is ~9-fold higher than MPAF, strongly suggesting that the variant is a benign polymorphism. The variant, c.869G>A, has also been reported in the literature in individuals affected with (suspected) Li-Fraumeni Syndrome and various tumor phenotypes, however, without strong evidence for causality. Multiple publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant overall did not decrease Tp53 expression, transcription activity, and function measured at the cellular level (e.g. Quesnel_1999, Zerdoumi_2017, Kotler_2018). Fifteen other submitters, including one expert panel (ClinGen TP53 Variant Curation Expert Panel) have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=8), likely benign (n=3) / benign (n=4; including the expert panel). 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 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002550936.4

#	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 3, 2024

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