NM_000546.6(TP53):c.188C>T (p.Ala63Val) AND Li-Fraumeni syndrome 1

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Apr 12, 2021
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:: RCV000663264.5

Allele description [Variation Report for NM_000546.6(TP53):c.188C>T (p.Ala63Val)]

NM_000546.6(TP53):c.188C>T (p.Ala63Val)

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.188C>T (p.Ala63Val)

Other names:

p.A63V:GCT>GTT

HGVS:

NC_000017.11:g.7676181G>A
NG_017013.2:g.16370C>T
NM_000546.6:c.188C>TMANE SELECT
NM_001126112.3:c.188C>T
NM_001126113.3:c.188C>T
NM_001126114.3:c.188C>T
NM_001126118.2:c.71C>T
NM_001276695.3:c.71C>T
NM_001276696.3:c.71C>T
NM_001276760.3:c.71C>T
NM_001276761.3:c.71C>T
NP_000537.3:p.Ala63Val
NP_000537.3:p.Ala63Val
NP_001119584.1:p.Ala63Val
NP_001119585.1:p.Ala63Val
NP_001119586.1:p.Ala63Val
NP_001119590.1:p.Ala24Val
NP_001263624.1:p.Ala24Val
NP_001263625.1:p.Ala24Val
NP_001263689.1:p.Ala24Val
NP_001263690.1:p.Ala24Val
LRG_321t1:c.188C>T
LRG_321t2:c.188C>T
LRG_321:g.16370C>T
LRG_321p1:p.Ala63Val
NC_000017.10:g.7579499G>A
NM_000546.4:c.188C>T
NM_000546.5:c.188C>T
NM_001126112.2(TP53):c.188C>T
P04637:p.Ala63Val
p.A63V

Protein change:

A24V

Links:

UniProtKB: P04637#VAR_044590; dbSNP: rs372201428

NCBI 1000 Genomes Browser:

rs372201428

Molecular consequence:

NM_000546.6:c.188C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.188C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.188C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.188C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.71C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.71C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.71C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.71C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.71C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Li-Fraumeni syndrome 1 (LFS)
Identifiers:: Gene: 553989; MedGen: C1835398; Orphanet: 524; OMIM: 151623

Recent activity

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Zinc metalloprotease [Symbiodinium microadriaticum]
Zinc metalloprotease [Symbiodinium microadriaticum]
gi|1129203235|gb|OLQ05902.1||gnl|WG X|Smic10819_prot

Protein
JGI_CAAK8245.fwd NIH_XGC_tropBrn3 Xenopus tropicalis cDNA clone IMAGE:7658999 5'...
JGI_CAAK8245.fwd NIH_XGC_tropBrn3 Xenopus tropicalis cDNA clone IMAGE:7658999 5', mRNA sequence
gi|58489871|gnl|dbEST|27537435|gb|C 29.1|

Nucleotide
CR574731 XGC-tailbud-head Xenopus tropicalis cDNA clone THdA037a11 5', mRNA sequ...
CR574731 XGC-tailbud-head Xenopus tropicalis cDNA clone THdA037a11 5', mRNA sequence
gi|50462157|gnl|dbEST|24659939|emb| 731.1|

Nucleotide
BX730449 XGC-tadpole Xenopus tropicalis cDNA clone TTpA044m09 5', mRNA sequence
BX730449 XGC-tadpole Xenopus tropicalis cDNA clone TTpA044m09 5', mRNA sequence
gi|38403190|gnl|dbEST|20447583|emb| 449.1|

Nucleotide
JGI_XZT9283.rev NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7587451 3',...
JGI_XZT9283.rev NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7587451 3', mRNA sequence
gi|74278480|gnl|dbEST|31354009|gb|C 39.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000786495	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (May 14, 2018)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12826609, 28861920, 18199664 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV001737942	ClinGen TP53 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen TP53 ACMG Specifications v1)	Likely benign (Apr 12, 2021)	germline	curation	Citation Link,
SCV004017876	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Uncertain significance (Apr 11, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000786495

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(May 14, 2018)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf,

Citation Link,

SCV001737942

ClinGen TP53 Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen TP53 ACMG Specifications v1)

Likely benign
(Apr 12, 2021)

germline

curation

Citation Link,

SCV004017876

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Uncertain significance
(Apr 11, 2023)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	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	curation

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 (3)

Details of each submission

From Counsyl, SCV000786495.2

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

#	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 ClinGen TP53 Variant Curation Expert Panel, ClinGen, SCV001737942.1

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

Description

Transactivation assays show [retained/supertransactivation] function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting: internal laboratory contributor (SCV000545312.6). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). In summary, TP53 c.188C>T (p.Ala63Val) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BS2, BP4.

#	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 Myriad Genetics, Inc., SCV004017876.1

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

Description

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

#	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

Last Updated: Nov 10, 2024

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