NM_000546.6(TP53):c.665C>T (p.Pro222Leu) AND Li-Fraumeni syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 8, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000148907.27

Allele description [Variation Report for NM_000546.6(TP53):c.665C>T (p.Pro222Leu)]

NM_000546.6(TP53):c.665C>T (p.Pro222Leu)

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.665C>T (p.Pro222Leu)

Other names:

p.P222L:CCG>CTG

HGVS:

NC_000017.11:g.7674866G>A
NG_017013.2:g.17685C>T
NM_000546.6:c.665C>TMANE SELECT
NM_001126112.3:c.665C>T
NM_001126113.3:c.665C>T
NM_001126114.3:c.665C>T
NM_001126115.2:c.269C>T
NM_001126116.2:c.269C>T
NM_001126117.2:c.269C>T
NM_001126118.2:c.548C>T
NM_001276695.3:c.548C>T
NM_001276696.3:c.548C>T
NM_001276697.3:c.188C>T
NM_001276698.3:c.188C>T
NM_001276699.3:c.188C>T
NM_001276760.3:c.548C>T
NM_001276761.3:c.548C>T
NP_000537.3:p.Pro222Leu
NP_000537.3:p.Pro222Leu
NP_001119584.1:p.Pro222Leu
NP_001119585.1:p.Pro222Leu
NP_001119586.1:p.Pro222Leu
NP_001119587.1:p.Pro90Leu
NP_001119588.1:p.Pro90Leu
NP_001119589.1:p.Pro90Leu
NP_001119590.1:p.Pro183Leu
NP_001263624.1:p.Pro183Leu
NP_001263625.1:p.Pro183Leu
NP_001263626.1:p.Pro63Leu
NP_001263627.1:p.Pro63Leu
NP_001263628.1:p.Pro63Leu
NP_001263689.1:p.Pro183Leu
NP_001263690.1:p.Pro183Leu
LRG_321t1:c.665C>T
LRG_321:g.17685C>T
LRG_321p1:p.Pro222Leu
NC_000017.10:g.7578184G>A
NM_000546.4:c.665C>T
NM_000546.5:c.665C>T
P04637:p.Pro222Leu
p.P222L

Protein change:

P183L

Links:

UniProtKB: P04637#VAR_045125; dbSNP: rs146340390

NCBI 1000 Genomes Browser:

rs146340390

Molecular consequence:

NM_000546.6:c.665C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.665C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.665C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.665C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.269C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.269C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.269C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.548C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.548C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.548C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.188C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.188C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.188C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.548C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.548C>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190653	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Likely benign (Jun 1, 2014)	germline	research
SCV000254634	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 8, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004823775	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 20, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 12826609, 15781620, 17724467, 20505364, 20522432, 23484829, 23897043, 25980754, 29979965, 30224644, 35323354, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190653

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

no assertion criteria provided

Likely benign
(Jun 1, 2014)

germline

research

SCV000254634

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Jan 8, 2024)

germline

clinical testing

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

SCV004823775

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 20, 2023)

germline

clinical testing

PubMed (12)
[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	6	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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

See all PubMed Citations (13)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190653.1

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000254634.11

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

#	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 All of Us Research Program, National Institutes of Health, SCV004823775.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (12)

Description

This missense variant replaces proline with leucine at codon 222 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Yeast and mammalian cell studies reported this variant to be functional, with some temperature-sensitive effects observed in yeast (PMID: 12826609, 15781620, 17724467, 20505364, 23897043, 29979965, 30224644). This variant has been reported in an individual with childhood-onset rhabdomyosarcoma (PMID: 20522432) and in an individual affected with early-onset breast cancer meeting the Chompret criteria (PMID: 35323354). This variant has also been observed in an individual affected with Li-Fraumeni syndrome who has a pathogenic p.Arg267Trp variant in the same gene (PMID: 23484829), and an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 6/282714 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		6	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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