NM_000546.6(TP53):c.388C>T (p.Leu130Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jun 30, 2022
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:: RCV000571787.8

Allele description [Variation Report for NM_000546.6(TP53):c.388C>T (p.Leu130Phe)]

NM_000546.6(TP53):c.388C>T (p.Leu130Phe)

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.388C>T (p.Leu130Phe)

HGVS:

NC_000017.11:g.7675224G>A
NG_017013.2:g.17327C>T
NM_000546.6:c.388C>TMANE SELECT
NM_001126112.3:c.388C>T
NM_001126113.3:c.388C>T
NM_001126114.3:c.388C>T
NM_001126115.2:c.-9C>T
NM_001126116.2:c.-9C>T
NM_001126117.2:c.-9C>T
NM_001126118.2:c.271C>T
NM_001276695.3:c.271C>T
NM_001276696.3:c.271C>T
NM_001276697.3:c.-90C>T
NM_001276698.3:c.-90C>T
NM_001276699.3:c.-90C>T
NM_001276760.3:c.271C>T
NM_001276761.3:c.271C>T
NP_000537.3:p.Leu130Phe
NP_000537.3:p.Leu130Phe
NP_001119584.1:p.Leu130Phe
NP_001119585.1:p.Leu130Phe
NP_001119586.1:p.Leu130Phe
NP_001119590.1:p.Leu91Phe
NP_001263624.1:p.Leu91Phe
NP_001263625.1:p.Leu91Phe
NP_001263689.1:p.Leu91Phe
NP_001263690.1:p.Leu91Phe
LRG_321t1:c.388C>T
LRG_321:g.17327C>T
LRG_321p1:p.Leu130Phe
NC_000017.10:g.7578542G>A
NM_000546.4:c.388C>T
NM_000546.5:c.388C>T
P04637:p.Leu130Phe

Protein change:

L130F

Links:

UniProtKB: P04637#VAR_044730; dbSNP: rs863224683

NCBI 1000 Genomes Browser:

rs863224683

Molecular consequence:

NM_001126115.2:c.-9C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001126116.2:c.-9C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001126117.2:c.-9C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276697.3:c.-90C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276698.3:c.-90C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276699.3:c.-90C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.388C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.388C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.388C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.388C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.271C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.271C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.271C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.271C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.271C>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000664438	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 21, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11332399, 19468865, 30224644, 33471991 Citation Link,
SCV002582094	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004360009	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 30, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11332399, 19468865, 27553368, 29979965, 30224644, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000664438

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 21, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV002582094

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 18, 2022)

germline

clinical testing

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

SCV004360009

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 30, 2022)

germline

clinical testing

PubMed (7)
[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
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sensitivity and predictive value of criteria for p53 germline mutation screening.

Chompret A, Abel A, Stoppa-Lyonnet D, Brugiéres L, Pagés S, Feunteun J, Bonaïti-Pellié C.

J Med Genet. 2001 Jan;38(1):43-7. No abstract available.

PubMed [citation]

PMID:: 11332399
PMCID:: PMC1734716

TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset.

Pinto C, Veiga I, Pinheiro M, Peixoto A, Pinto A, Lopes JM, Reis RM, Oliveira C, Baptista M, Roque L, Regateiro F, Cirnes L, Hofstra RM, Seruca R, Castedo S, Teixeira MR.

Fam Cancer. 2009;8(4):383-90. doi: 10.1007/s10689-009-9251-y. Epub 2009 May 26.

PubMed [citation]

PMID:: 19468865

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000664438.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.L130F pathogenic mutation (also known as c.388C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 388. The leucine at codon 130 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in a patient diagnosed with breast cancer at age 31y who has no reported family history of cancer, in a female patient diagnosed with sarcoma and rectal cancer at age 39y who has a family history of pancreatic cancer, and in a patient diagnosed with colorectal cancer at age 17y who has a family history of three paternal aunts with early-onset breast cancer diagnosed at ages 23y, 37y, and 40y (Chompret A et al. J Med Genet. 2001 Jan;38(1):43-7; Pinto C et al. Fam Cancer. 2009;8(4):383-90; Pinto P et al. Breast Cancer Res Treat. 2016 Sep;159(2):245-56). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Chompret A et al. J Med Genet. 2001 Jan;38(1):43-7). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 Genome-Nilou Lab, SCV002582094.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV004360009.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces leucine with phenylalanine at codon 130 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant is non-functional in yeast transactivation assays (IARC database; PMID: 12826609), non-functional in human cell proliferation assays (PMID: 29979965), and exhibits dominant-negative effect and loss of function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with breast cancer at the age of 31 (PMID: 11332399), an individual affected with sarcoma and rectal cancer at the age of 39 with a family history of pancreatic cancer (PMID: 19468865), and an individual affected with colorectal cancer at the age of 17 with a family history of early-onset breast cancer (PMID: 27553368). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The 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: Sep 29, 2024

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