NM_000546.5(TP53):c.646G>A (p.Val216Met) AND Li-Fraumeni syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 17, 2020
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:: RCV000168150.7

Allele description

NM_000546.5(TP53):c.646G>A (p.Val216Met)

Gene:

TP53:tumor protein p53 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000546.5(TP53):c.646G>A (p.Val216Met)

Other names:

p.V216M:GTG>ATG

HGVS:

NC_000017.11:g.7674885C>T
NG_017013.2:g.17666G>A
NM_000546.5:c.646G>A
NM_001126112.2:c.646G>A
NM_001126113.2:c.646G>A
NM_001126114.2:c.646G>A
NM_001126115.1:c.250G>A
NM_001126116.1:c.250G>A
NM_001126117.1:c.250G>A
NM_001126118.1:c.529G>A
NM_001276695.2:c.529G>A
NM_001276696.2:c.529G>A
NM_001276697.2:c.169G>A
NM_001276698.2:c.169G>A
NM_001276699.2:c.169G>A
NM_001276760.2:c.529G>A
NM_001276761.2:c.529G>A
NP_000537.3:p.Val216Met
NP_001119584.1:p.Val216Met
NP_001119585.1:p.Val216Met
NP_001119586.1:p.Val216Met
NP_001119587.1:p.Val84Met
NP_001119588.1:p.Val84Met
NP_001119589.1:p.Val84Met
NP_001119590.1:p.Val177Met
NP_001263624.1:p.Val177Met
NP_001263625.1:p.Val177Met
NP_001263626.1:p.Val57Met
NP_001263627.1:p.Val57Met
NP_001263628.1:p.Val57Met
NP_001263689.1:p.Val177Met
NP_001263690.1:p.Val177Met
LRG_321t1:c.646G>A
LRG_321t2:c.646G>A
LRG_321t3:c.646G>A
LRG_321t4:c.646G>A
LRG_321t5:c.250G>A
LRG_321t6:c.250G>A
LRG_321t7:c.250G>A
LRG_321t8:c.529G>A
LRG_321:g.17666G>A
LRG_321:p.Val216Met
LRG_321p1:p.Val216Met
LRG_321p3:p.Val216Met
LRG_321p4:p.Val216Met
LRG_321p5:p.Val84Met
LRG_321p6:p.Val84Met
LRG_321p7:p.Val84Met
LRG_321p8:p.Val177Met
NC_000017.10:g.7578203C>T
NM_000546.4:c.646G>A
P04637:p.Val216Met

Protein change:

V177M

Links:

UniProtKB: P04637#VAR_005956; dbSNP: rs730882025

NCBI 1000 Genomes Browser:

rs730882025

Molecular consequence:

NM_000546.5:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.2:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.2:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.2:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.1:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.1:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.1:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.1:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.2:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.2:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.2:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.2:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.2:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.2:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.2:c.529G>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

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Homo sapiens coiled-coil domain containing 149 (CCDC149), transcript variant 2, mRNA
gi|1060604676|ref|NM_001130726.3|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000218811	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 11, 2019)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 25669829, 26014290, 24549055, 12826609, 17724467, 21232794, 28492532
SCV001449165	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 17, 2020)	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

SCV000218811

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 11, 2019)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001449165

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 17, 2020)

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	yes	1	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

Phase I study of pazopanib and vorinostat: a therapeutic approach for inhibiting mutant p53-mediated angiogenesis and facilitating mutant p53 degradation.

Fu S, Hou MM, Naing A, Janku F, Hess K, Zinner R, Subbiah V, Hong D, Wheler J, Piha-Paul S, Tsimberidou A, Karp D, Araujo D, Kee B, Hwu P, Wolff R, Kurzrock R, Meric-Bernstam F.

Ann Oncol. 2015 May;26(5):1012-1018. doi: 10.1093/annonc/mdv066. Epub 2015 Feb 10.

PubMed [citation]

PMID:: 25669829
PMCID:: PMC6279067

Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers.

Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, Gauthier-Villars M, Stoppa-Lyonnet D, Consolino E, Brugières L, Caron O, Benusiglio PR, Bressac-de Paillerets B, Bonadona V, Bonaïti-Pellié C, Tinat J, Baert-Desurmont S, Frebourg T.

J Clin Oncol. 2015 Jul 20;33(21):2345-52. doi: 10.1200/JCO.2014.59.5728. Epub 2015 May 26.

PubMed [citation]

PMID:: 26014290

See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000218811.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces valine with methionine at codon 216 of the TP53 protein (p.Val216Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 26014290, Invitae). Additionally, this variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 24549055, 25669829). Clinvar contains an entry for this variant (Variation ID: 182965). Experimental studies in yeast have shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 17724467, 21232794). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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 Cancer Variant Interpretation Group UK, Institute of Cancer Research, London, SCV001449165.1

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

Description

Data included in classification: UK family: 4 generation classic LFS family including multiple sarcomas Literature: (i) Bougeard 2015: 1 child (?age) with ACC , (ii) Zerdoumi 2017: 1 adult male age 30y with alveloar rhabdo age 3y & soft tissue sarcoma age 17y. Both index cases & fulfil Chompret (nil known re FHx) (PS4_mod). This variant is absent from gnomAD (PM2_sup). AGvGD = C15 , Bayes Del = 0.5501. PP3_sup. x81 somatic in IARC (PM1_sup). Kato â€“ non functional, DNE + LOF (Giacomelli) , Kotler - RFS score = 0.2 â†’ compromised function. (PS3_strong)

#	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		1	not provided	not provided	not provided

Last Updated: Apr 13, 2021

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