NM_000546.6(TP53):c.873G>C (p.Lys291Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 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:: RCV000774787.8

Allele description [Variation Report for NM_000546.6(TP53):c.873G>C (p.Lys291Asn)]

NM_000546.6(TP53):c.873G>C (p.Lys291Asn)

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.873G>C (p.Lys291Asn)

HGVS:

NC_000017.11:g.7673747C>G
NG_017013.2:g.18804G>C
NM_000546.6:c.873G>CMANE SELECT
NM_001126112.3:c.873G>C
NM_001126113.3:c.873G>C
NM_001126114.3:c.873G>C
NM_001126115.2:c.477G>C
NM_001126116.2:c.477G>C
NM_001126117.2:c.477G>C
NM_001126118.2:c.756G>C
NM_001276695.3:c.756G>C
NM_001276696.3:c.756G>C
NM_001276697.3:c.396G>C
NM_001276698.3:c.396G>C
NM_001276699.3:c.396G>C
NM_001276760.3:c.756G>C
NM_001276761.3:c.756G>C
NP_000537.3:p.Lys291Asn
NP_000537.3:p.Lys291Asn
NP_001119584.1:p.Lys291Asn
NP_001119585.1:p.Lys291Asn
NP_001119586.1:p.Lys291Asn
NP_001119587.1:p.Lys159Asn
NP_001119588.1:p.Lys159Asn
NP_001119589.1:p.Lys159Asn
NP_001119590.1:p.Lys252Asn
NP_001263624.1:p.Lys252Asn
NP_001263625.1:p.Lys252Asn
NP_001263626.1:p.Lys132Asn
NP_001263627.1:p.Lys132Asn
NP_001263628.1:p.Lys132Asn
NP_001263689.1:p.Lys252Asn
NP_001263690.1:p.Lys252Asn
LRG_321t1:c.873G>C
LRG_321:g.18804G>C
LRG_321p1:p.Lys291Asn
NC_000017.10:g.7577065C>G
NM_000546.4:c.873G>C
NM_000546.5:c.873G>C

Protein change:

K132N

Links:

dbSNP: rs372613518

NCBI 1000 Genomes Browser:

rs372613518

Molecular consequence:

NM_000546.6:c.873G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.873G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.873G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.873G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.477G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.477G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.477G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.756G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.756G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.756G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.396G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.396G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.396G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.756G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.756G>C - 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
SCV000908786	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 31, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12826609, 29979965, 30224644, 25741868
SCV002581986	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]
SCV002682021	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Jan 15, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000908786

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 31, 2021)

germline

clinical testing

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

SCV002581986

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]

SCV002682021

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Jan 15, 2021)

germline

clinical testing

Citation Link

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 Color Diagnostics, LLC DBA Color Health, SCV000908786.2

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

Description

This missense variant replaces lysine with asparagine at codon 291 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental studies have shown that this variant functions as wild-type TP53 in yeast-based transcriptional transactivation assays, and human cell growth and proliferation assays (PMID: 30224644, 29979965, 12826609). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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

From Genome-Nilou Lab, SCV002581986.1

#	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 Ambry Genetics, SCV002682021.2

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

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

Last Updated: Sep 29, 2024

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