U.S. flag

An official website of the United States government

NM_000546.6(TP53):c.646G>A (p.Val216Met) AND Li-Fraumeni syndrome

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Aug 28, 2023
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:
RCV000168150.17

Allele description [Variation Report for NM_000546.6(TP53):c.646G>A (p.Val216Met)]

NM_000546.6(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_000546.6(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_000546.6:c.646G>AMANE SELECT
  • NM_001126112.3:c.646G>A
  • NM_001126113.3:c.646G>A
  • NM_001126114.3:c.646G>A
  • NM_001126115.2:c.250G>A
  • NM_001126116.2:c.250G>A
  • NM_001126117.2:c.250G>A
  • NM_001126118.2:c.529G>A
  • NM_001276695.3:c.529G>A
  • NM_001276696.3:c.529G>A
  • NM_001276697.3:c.169G>A
  • NM_001276698.3:c.169G>A
  • NM_001276699.3:c.169G>A
  • NM_001276760.3:c.529G>A
  • NM_001276761.3:c.529G>A
  • NP_000537.3:p.Val216Met
  • 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_321:g.17666G>A
  • LRG_321p1:p.Val216Met
  • NC_000017.10:g.7578203C>T
  • NM_000546.4:c.646G>A
  • NM_000546.5:c.646G>A
  • P04637:p.Val216Met
Protein change:
V177M
Links:
UniProtKB: P04637#VAR_005956; dbSNP: rs730882025
NCBI 1000 Genomes Browser:
rs730882025
Molecular consequence:
  • NM_000546.6:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.2:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.2:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.2:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.3:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.3:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.3:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3: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
SCV000218811Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Aug 28, 2023) 		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]

SCV004847704Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Apr 2, 2019) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

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

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

Kotler E, Shani O, Goldfeld G, Lotan-Pompan M, Tarcic O, Gershoni A, Hopf TA, Marks DS, Oren M, Segal E.

Mol Cell. 2018 Jul 5;71(1):178-190.e8. doi: 10.1016/j.molcel.2018.06.012. Erratum in: Mol Cell. 2018 Sep 6;71(5):873. doi: 10.1016/j.molcel.2018.08.013.

PubMed [citation]
PMID:
29979965
See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000218811.12

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 182965). This missense change has been observed in individuals with breast and/or ovarian cancer and clinical features of Li-Fraumeni syndrome (PMID: 24549055, 25669829, 26014290; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 216 of the TP53 protein (p.Val216Met). For these reasons, this variant has been classified as 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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847704.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The p.Val216Met variant in TP53 has been reported in two individuals with TP53-related tumors and one individual with a family history of TP53-related tumors (Castera 2014, Bougeard 2015, Zerdoumi 2017). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 182965). It has also been reported as a common somatic mutation across multiple tumor types (COSMIC Database, https://cancer.sanger.ac.uk/cosmic/). In vitro functional studies provide some evidence that this variant impacts protein transactivation function (Slovackova 2010, Zerdoumi 2017); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis support that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP3, PS4_Supporting.

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

Last Updated: Sep 29, 2024