NM_000546.6(TP53):c.665C>T (p.Pro222Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jun 20, 2023
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:: RCV000161032.25

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]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

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5-hydroxytryptamine receptor 2C isoform a precursor [Homo sapiens]
5-hydroxytryptamine receptor 2C isoform a precursor [Homo sapiens]
gi|4504541|ref|NP_000859.1|

Protein
Fam25a family with sequence similarity 25, member A [Mus musculus]
Fam25a family with sequence similarity 25, member A [Mus musculus]
Gene ID:69134

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000215615	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Sep 28, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17724467, 20505364, 25637381, 28230820, 28861920 Citation Link,
SCV000822208	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000903062	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 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

SCV000215615

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Sep 28, 2020)

germline

clinical testing

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

Citation Link,

SCV000822208

GeneKor MSA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 1, 2018)

germline

clinical testing

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

SCV000903062

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 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	yes	not provided	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

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

The distribution of TP53 gene polymorphisms in chronic lymphocytic leukemia patients, sufferers of Chornobyl nuclear power plant accident.

Bilous NI, Abramenko IV, Chumak AA, Dyagil IS, Martina ZV.

Exp Oncol. 2016 Dec;38(4):252-256.

PubMed [citation]

PMID:: 28230820

See all PubMed Citations (15)

Details of each submission

From Ambry Genetics, SCV000215615.8

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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 GeneKor MSA, SCV000822208.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000903062.4

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

Last Updated: Nov 3, 2024

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