NM_000546.6(TP53):c.245C>T (p.Pro82Leu) AND Li-Fraumeni syndrome

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Aug 28, 2019
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000205955.18

Allele description [Variation Report for NM_000546.6(TP53):c.245C>T (p.Pro82Leu)]

NM_000546.6(TP53):c.245C>T (p.Pro82Leu)

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.245C>T (p.Pro82Leu)

Other names:

p.P82L:CCG>CTG

HGVS:

NC_000017.11:g.7676124G>A
NG_017013.2:g.16427C>T
NM_000546.6:c.245C>TMANE SELECT
NM_001126112.3:c.245C>T
NM_001126113.3:c.245C>T
NM_001126114.3:c.245C>T
NM_001126118.2:c.128C>T
NM_001276695.3:c.128C>T
NM_001276696.3:c.128C>T
NM_001276760.3:c.128C>T
NM_001276761.3:c.128C>T
NM_001407262.1:c.245C>T
NM_001407263.1:c.128C>T
NM_001407264.1:c.245C>T
NM_001407265.1:c.128C>T
NM_001407266.1:c.245C>T
NM_001407267.1:c.128C>T
NM_001407268.1:c.245C>T
NM_001407269.1:c.128C>T
NM_001407270.1:c.245C>T
NM_001407271.1:c.128C>T
NP_000537.3:p.Pro82Leu
NP_000537.3:p.Pro82Leu
NP_001119584.1:p.Pro82Leu
NP_001119584.1:p.Pro82Leu
NP_001119585.1:p.Pro82Leu
NP_001119585.1:p.Pro82Leu
NP_001119586.1:p.Pro82Leu
NP_001119586.1:p.Pro82Leu
NP_001119590.1:p.Pro43Leu
NP_001119590.1:p.Pro43Leu
NP_001263624.1:p.Pro43Leu
NP_001263625.1:p.Pro43Leu
NP_001263689.1:p.Pro43Leu
NP_001263690.1:p.Pro43Leu
NP_001394191.1:p.Pro82Leu
NP_001394192.1:p.Pro43Leu
NP_001394193.1:p.Pro82Leu
NP_001394194.1:p.Pro43Leu
NP_001394195.1:p.Pro82Leu
NP_001394196.1:p.Pro43Leu
NP_001394197.1:p.Pro82Leu
NP_001394198.1:p.Pro43Leu
NP_001394199.1:p.Pro82Leu
NP_001394200.1:p.Pro43Leu
LRG_321t1:c.245C>T
LRG_321t2:c.245C>T
LRG_321t3:c.245C>T
LRG_321t4:c.245C>T
LRG_321t7:c.-909C>T
LRG_321t8:c.128C>T
LRG_321:g.16427C>T
LRG_321:p.Pro82Leu
LRG_321p1:p.Pro82Leu
LRG_321p3:p.Pro82Leu
LRG_321p4:p.Pro82Leu
LRG_321p8:p.Pro43Leu
NC_000017.10:g.7579442G>A
NM_000546.4:c.245C>T
NM_000546.5(TP53):c.245C>T
NM_000546.5:c.245C>T
NM_001126112.2:c.245C>T
NM_001126113.2:c.245C>T
NM_001126114.2:c.245C>T
NM_001126117.1:c.-909C>T
NM_001126118.1:c.128C>T
NR_176326.1:n.387C>T
P04637:p.Pro82Leu
p.P82L

Protein change:

P43L

Links:

UniProtKB: P04637#VAR_044621; dbSNP: rs534447939

NCBI 1000 Genomes Browser:

rs534447939

Molecular consequence:

NM_000546.6:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.128C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.128C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.128C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.128C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.128C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407262.1:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407263.1:c.128C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407264.1:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407265.1:c.128C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407266.1:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407267.1:c.128C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407268.1:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407269.1:c.128C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407270.1:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407271.1:c.128C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_176326.1:n.387C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000259808	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 11, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 8710380, 28202063, 33309985, 12826609, 17606709, 20128691, 21343334, 24256616, 30224644, 28492532
SCV001142533	ClinGen TP53 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen TP53 ACMG Specifications v1)	Likely benign (Aug 28, 2019)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 12826609, 30224644 Citation Link,
SCV004823828	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Benign (Oct 30, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000259808

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 11, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV001142533

ClinGen TP53 Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen TP53 ACMG Specifications v1)

Likely benign
(Aug 28, 2019)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004823828

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Benign
(Oct 30, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	5	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

A novel p53 germline alteration identified in a late onset breast cancer kindred.

Sun XF, Johannsson O, Håkansson S, Sellberg G, Nordenskjöld B, Olsson H, Borg A.

Oncogene. 1996 Jul 18;13(2):407-11.

PubMed [citation]

PMID:: 8710380

Next-generation sequencing in familial breast cancer patients from Lebanon.

Jalkh N, Chouery E, Haidar Z, Khater C, Atallah D, Ali H, Marafie MJ, Al-Mulla MR, Al-Mulla F, Megarbane A.

BMC Med Genomics. 2017 Feb 15;10(1):8. doi: 10.1186/s12920-017-0244-7.

PubMed [citation]

PMID:: 28202063
PMCID:: PMC5312584

See all PubMed Citations (11)

Details of each submission

From Invitae, SCV000259808.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 82 of the TP53 protein (p.Pro82Leu). This variant is present in population databases (rs534447939, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and colon cancer (PMID: 8710380, 28202063, 33309985). ClinVar contains an entry for this variant (Variation ID: 182946). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 17606709, 20128691, 21343334, 24256616, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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

From ClinGen TP53 Variant Curation Expert Panel, ClinGen, SCV001142533.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, TP53 c.245C>T; p.Pro82Leu meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4 and BS3.

#	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, SCV004823828.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	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	108544	not provided	not provided		5	not provided	not provided	not provided

Last Updated: May 26, 2024

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