NM_000546.6(TP53):c.379T>A (p.Ser127Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 18, 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:: RCV001021179.6

Allele description [Variation Report for NM_000546.6(TP53):c.379T>A (p.Ser127Thr)]

NM_000546.6(TP53):c.379T>A (p.Ser127Thr)

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.379T>A (p.Ser127Thr)

HGVS:

NC_000017.11:g.7675233A>T
NG_017013.2:g.17318T>A
NM_000546.6:c.379T>AMANE SELECT
NM_001126112.3:c.379T>A
NM_001126113.3:c.379T>A
NM_001126114.3:c.379T>A
NM_001126115.2:c.-18T>A
NM_001126116.2:c.-18T>A
NM_001126117.2:c.-18T>A
NM_001126118.2:c.262T>A
NM_001276695.3:c.262T>A
NM_001276696.3:c.262T>A
NM_001276697.3:c.-99T>A
NM_001276698.3:c.-99T>A
NM_001276699.3:c.-99T>A
NM_001276760.3:c.262T>A
NM_001276761.3:c.262T>A
NP_000537.3:p.Ser127Thr
NP_001119584.1:p.Ser127Thr
NP_001119585.1:p.Ser127Thr
NP_001119586.1:p.Ser127Thr
NP_001119590.1:p.Ser88Thr
NP_001263624.1:p.Ser88Thr
NP_001263625.1:p.Ser88Thr
NP_001263689.1:p.Ser88Thr
NP_001263690.1:p.Ser88Thr
LRG_321t1:c.379T>A
LRG_321:g.17318T>A
NC_000017.10:g.7578551A>T
NM_000546.4:c.379T>A
NM_000546.5:c.379T>A

Protein change:

S127T

Links:

dbSNP: rs1597371694

NCBI 1000 Genomes Browser:

rs1597371694

Molecular consequence:

NM_001126115.2:c.-18T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001126116.2:c.-18T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001126117.2:c.-18T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276697.3:c.-99T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276698.3:c.-99T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276699.3:c.-99T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.379T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.379T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.379T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.379T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.262T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.262T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.262T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.262T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.262T>A - 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
SCV001182760	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 3, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12826609, 29979965, 30224644 Citation Link,
SCV002582097	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001182760

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 3, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV002582097

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]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	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

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 (4)

Details of each submission

From Ambry Genetics, SCV001182760.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.S127T pathogenic mutation (also known as c.379T>A), located in coding exon 4 of the TP53 gene, results from a T to A substitution at nucleotide position 379. The serine at codon 127 is replaced by threonine, an amino acid with similar properties. 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). 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. 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, SCV002582097.1

#	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

Last Updated: Sep 29, 2024

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