NM_000546.6(TP53):c.643A>T (p.Ser215Cys) AND Li-Fraumeni syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 17, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003103297.2

Allele description [Variation Report for NM_000546.6(TP53):c.643A>T (p.Ser215Cys)]

NM_000546.6(TP53):c.643A>T (p.Ser215Cys)

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.643A>T (p.Ser215Cys)

HGVS:

NC_000017.11:g.7674888T>A
NG_017013.2:g.17663A>T
NM_000546.6:c.643A>TMANE SELECT
NM_001126112.3:c.643A>T
NM_001126113.3:c.643A>T
NM_001126114.3:c.643A>T
NM_001126115.2:c.247A>T
NM_001126116.2:c.247A>T
NM_001126117.2:c.247A>T
NM_001126118.2:c.526A>T
NM_001276695.3:c.526A>T
NM_001276696.3:c.526A>T
NM_001276697.3:c.166A>T
NM_001276698.3:c.166A>T
NM_001276699.3:c.166A>T
NM_001276760.3:c.526A>T
NM_001276761.3:c.526A>T
NM_001407262.1:c.643A>T
NM_001407263.1:c.526A>T
NM_001407264.1:c.643A>T
NM_001407265.1:c.526A>T
NM_001407266.1:c.643A>T
NM_001407267.1:c.526A>T
NM_001407268.1:c.643A>T
NM_001407269.1:c.526A>T
NM_001407270.1:c.643A>T
NM_001407271.1:c.526A>T
NP_000537.3:p.Ser215Cys
NP_000537.3:p.Ser215Cys
NP_001119584.1:p.Ser215Cys
NP_001119584.1:p.Ser215Cys
NP_001119585.1:p.Ser215Cys
NP_001119585.1:p.Ser215Cys
NP_001119586.1:p.Ser215Cys
NP_001119586.1:p.Ser215Cys
NP_001119587.1:p.Ser83Cys
NP_001119587.1:p.Ser83Cys
NP_001119588.1:p.Ser83Cys
NP_001119588.1:p.Ser83Cys
NP_001119589.1:p.Ser83Cys
NP_001119589.1:p.Ser83Cys
NP_001119590.1:p.Ser176Cys
NP_001119590.1:p.Ser176Cys
NP_001263624.1:p.Ser176Cys
NP_001263625.1:p.Ser176Cys
NP_001263626.1:p.Ser56Cys
NP_001263627.1:p.Ser56Cys
NP_001263628.1:p.Ser56Cys
NP_001263689.1:p.Ser176Cys
NP_001263690.1:p.Ser176Cys
NP_001394191.1:p.Ser215Cys
NP_001394192.1:p.Ser176Cys
NP_001394193.1:p.Ser215Cys
NP_001394194.1:p.Ser176Cys
NP_001394195.1:p.Ser215Cys
NP_001394196.1:p.Ser176Cys
NP_001394197.1:p.Ser215Cys
NP_001394198.1:p.Ser176Cys
NP_001394199.1:p.Ser215Cys
NP_001394200.1:p.Ser176Cys
LRG_321t1:c.643A>T
LRG_321t2:c.643A>T
LRG_321t3:c.643A>T
LRG_321t4:c.643A>T
LRG_321t5:c.247A>T
LRG_321t6:c.247A>T
LRG_321t7:c.247A>T
LRG_321t8:c.526A>T
LRG_321:g.17663A>T
LRG_321:p.Ser215Cys
LRG_321p1:p.Ser215Cys
LRG_321p3:p.Ser215Cys
LRG_321p4:p.Ser215Cys
LRG_321p5:p.Ser83Cys
LRG_321p6:p.Ser83Cys
LRG_321p7:p.Ser83Cys
LRG_321p8:p.Ser176Cys
NC_000017.10:g.7578206T>A
NM_000546.4:c.643A>T
NM_000546.5:c.643A>T
NM_001126112.2:c.643A>T
NM_001126113.2:c.643A>T
NM_001126114.2:c.643A>T
NM_001126115.1:c.247A>T
NM_001126116.1:c.247A>T
NM_001126117.1:c.247A>T
NM_001126118.1:c.526A>T

Protein change:

S176C

Molecular consequence:

NM_000546.6:c.643A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.643A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.643A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.643A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.247A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.247A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.247A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.526A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.526A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.526A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.166A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.166A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.166A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.526A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.526A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407262.1:c.643A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407263.1:c.526A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407264.1:c.643A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407265.1:c.526A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407266.1:c.643A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407267.1:c.526A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407268.1:c.643A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407269.1:c.526A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407270.1:c.643A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407271.1:c.526A>T - missense variant - [Sequence Ontology: SO:0001583]

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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LOC117406456 [Acipenser ruthenus]
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003240926	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12826609, 29979965, 30224644, 10229196, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003240926

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 17, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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 (5)

Details of each submission

From Invitae, SCV003240926.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 215 of the TP53 protein (p.Ser215Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 1753522). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 10229196). This variant disrupts the p.Ser215 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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

Last Updated: May 1, 2024

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