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

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:
1

Condition(s)

Name:
Li-Fraumeni syndrome (LFS)
Synonyms:
Sarcoma family syndrome of Li and Fraumeni
Identifiers:
MONDO: MONDO:0018875; MedGen: C0085390; OMIM: PS151623

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000218811Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Dec 11, 2019) 		germlineclinical testing

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

SCV001449165Cancer Variant Interpretation Group UK, Institute of Cancer Research, London
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Sep 17, 2020) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical 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 – non functional, DNE + LOF (Giacomelli) , Kotler - RFS score = 0.2 → compromised function. (PS3_strong)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Apr 13, 2021