NM_000546.6(TP53):c.742C>T (p.Arg248Trp) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: May 11, 2022
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:: RCV000213057.17

Allele description [Variation Report for NM_000546.6(TP53):c.742C>T (p.Arg248Trp)]

NM_000546.6(TP53):c.742C>T (p.Arg248Trp)

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.742C>T (p.Arg248Trp)

Other names:

p.R248W:CGG>TGG

HGVS:

NC_000017.11:g.7674221G>A
NG_017013.2:g.18330C>T
NM_000546.6:c.742C>TMANE SELECT
NM_001126112.3:c.742C>T
NM_001126113.3:c.742C>T
NM_001126114.3:c.742C>T
NM_001126115.2:c.346C>T
NM_001126116.2:c.346C>T
NM_001126117.2:c.346C>T
NM_001126118.2:c.625C>T
NM_001276695.3:c.625C>T
NM_001276696.3:c.625C>T
NM_001276697.3:c.265C>T
NM_001276698.3:c.265C>T
NM_001276699.3:c.265C>T
NM_001276760.3:c.625C>T
NM_001276761.3:c.625C>T
NP_000537.3:p.Arg248Trp
NP_000537.3:p.Arg248Trp
NP_001119584.1:p.Arg248Trp
NP_001119585.1:p.Arg248Trp
NP_001119586.1:p.Arg248Trp
NP_001119586.1:p.Arg248Trp
NP_001119587.1:p.Arg116Trp
NP_001119588.1:p.Arg116Trp
NP_001119589.1:p.Arg116Trp
NP_001119590.1:p.Arg209Trp
NP_001263624.1:p.Arg209Trp
NP_001263625.1:p.Arg209Trp
NP_001263626.1:p.Arg89Trp
NP_001263627.1:p.Arg89Trp
NP_001263628.1:p.Arg89Trp
NP_001263689.1:p.Arg209Trp
NP_001263690.1:p.Arg209Trp
LRG_321t1:c.742C>T
LRG_321t3:c.742C>T
LRG_321:g.18330C>T
LRG_321p1:p.Arg248Trp
LRG_321p3:p.Arg248Trp
NC_000017.10:g.7577539G>A
NM_000546.4:c.742C>T
NM_000546.5(TP53):c.742C>T
NM_000546.5:c.742C>T
NM_001126114.2:c.742C>T
P04637:p.Arg248Trp
p.R248W

Protein change:

R116W; ARG248TRP

Links:

UniProtKB: P04637#VAR_005984; OMIM: 191170.0001; dbSNP: rs121912651

NCBI 1000 Genomes Browser:

rs121912651

Molecular consequence:

NM_000546.6:c.742C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.742C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.742C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.742C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.346C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.346C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.346C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.625C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.625C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.625C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.265C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.265C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.265C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.625C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.625C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149644	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 11, 2022)	germline	clinical testing	Citation Link,
SCV001469327	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Oct 25, 2019)	unknown	clinical testing	PubMed (18) [See all records that cite these PMIDs] 29025599, 28724667, 27374712, 26787237, 26619011, 25925845, 25157968, 24651015, 24603336, 24573247, 24038938, 23950206, 23172776, 22713868, 21343334, 17606709, 20128691, 26467025
SCV001739798	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001905841	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001956921	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Constitutional mosaicism of a de novo TP53 mutation in a patient with bilateral choroid plexus carcinoma.

Trubicka J, Filipek I, Iwanowski P, Rydzanicz M, Grajkowska W, Piekutowska-Abramczuk D, Chrzanowska K, Karkucińska-Więckowska A, Iwanicka-Pronicka K, Pronicki M, Łastowska M, Płoski R, Dembowska-Bagińska B.

Cancer Genet. 2017 Oct;216-217:79-85. doi: 10.1016/j.cancergen.2017.07.001. Epub 2017 Jul 20.

PubMed [citation]

PMID:: 29025599

Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.

Sun J, Meng H, Yao L, Lv M, Bai J, Zhang J, Wang L, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xie Y.

Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. doi: 10.1158/1078-0432.CCR-16-3227. Epub 2017 Jul 19.

PubMed [citation]

PMID:: 28724667

See all PubMed Citations (18)

Details of each submission

From GeneDx, SCV000149644.16

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

Description

Observed in several individuals and families meeting Li-Fraumeni or Li-Fraumeni like criteria (Malkin et al., 1990, Birch et al., 1994, Hwang et al., 2003, Monti et al., 2007, Rossbach et al., 2008, Serra et al., 2013, Villani et al., 2016); Published functional studies demonstrate a damaging effect: non-functional transactivation, dominant-negative effect, loss of growth suppression activity (Kato et al., 2003, Willis et al., 2004, Grochova et al., 2008, Monti et al., 2011, Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8118819, 27501770, 26215675, 1978757, 12209590, 12610779, 27374712, 24603336, 16959974, 28387325, 28527674, 29979965, 25525159, 19378321, 30076369, 29324801, 20128691, 15280671, 17606709, 17724467, 14743206, 1565144, 25925845, 24651015, 26787237, 27714481, 22265402, 23950206, 9764816, 17427234, 27323394, 26223322, 25958320, 26703669, 23172776, 24573247, 21343334, 26681312, 28831167, 29025599, 28369373, 29077933, 28915717, 28356770, 28735817, 28624650, 29489754, 29730572, 30042819, 11051239, 28472496, 28724667, 29752822, 30092803, 29753700, 29961768, 30720243, 21686767, 31016814, 30840781, 30137042, 31081129, 15510160, 12826609, 29625052, 31105275, 31447099, 31775759, 32930885, 33818021, 32475984, 33300245, 30755392, 32658383, 32817165, 33245408, 33087929)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001469327.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. One de novo case with parental identity not confirmed.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001739798.3

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus, SCV001905841.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001956921.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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