NM_000546.6(TP53):c.949C>A (p.Gln317Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Feb 16, 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:: RCV000223439.14

Allele description [Variation Report for NM_000546.6(TP53):c.949C>A (p.Gln317Lys)]

NM_000546.6(TP53):c.949C>A (p.Gln317Lys)

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.949C>A (p.Gln317Lys)

Other names:

NM_000546.5(TP53):c.949C>A

HGVS:

NC_000017.11:g.7673579G>T
NG_017013.2:g.18972C>A
NM_000546.6:c.949C>AMANE SELECT
NM_001126112.3:c.949C>A
NM_001126113.3:c.949C>A
NM_001126114.3:c.949C>A
NM_001126115.2:c.553C>A
NM_001126116.2:c.553C>A
NM_001126117.2:c.553C>A
NM_001126118.2:c.832C>A
NM_001276695.3:c.832C>A
NM_001276696.3:c.832C>A
NM_001276697.3:c.472C>A
NM_001276698.3:c.472C>A
NM_001276699.3:c.472C>A
NM_001276760.3:c.832C>A
NM_001276761.3:c.832C>A
NP_000537.3:p.Gln317Lys
NP_000537.3:p.Gln317Lys
NP_001119584.1:p.Gln317Lys
NP_001119585.1:p.Gln317Lys
NP_001119586.1:p.Gln317Lys
NP_001119587.1:p.Gln185Lys
NP_001119588.1:p.Gln185Lys
NP_001119589.1:p.Gln185Lys
NP_001119590.1:p.Gln278Lys
NP_001263624.1:p.Gln278Lys
NP_001263625.1:p.Gln278Lys
NP_001263626.1:p.Gln158Lys
NP_001263627.1:p.Gln158Lys
NP_001263628.1:p.Gln158Lys
NP_001263689.1:p.Gln278Lys
NP_001263690.1:p.Gln278Lys
LRG_321t1:c.949C>A
LRG_321:g.18972C>A
LRG_321p1:p.Gln317Lys
NC_000017.10:g.7576897G>T
NM_000546.4:c.949C>A
NM_000546.5:c.949C>A
P04637:p.Gln317Lys

Protein change:

Q158K

Links:

UniProtKB: P04637#VAR_045500; dbSNP: rs764735889

NCBI 1000 Genomes Browser:

rs764735889

Molecular consequence:

NM_000546.6:c.949C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.949C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.949C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.949C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.553C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.553C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.553C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.832C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.832C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.832C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.472C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.472C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.472C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.832C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.832C>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
SCV000274731	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Mar 7, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000911369	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 16, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12826609, 25527155, 30224644, 33471991, 25741868
SCV002532730	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jun 22, 2021)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 25527155, 33471991, 30441849, 12826609, 30224644 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000274731

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Mar 7, 2019)

germline

clinical testing

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

Citation Link,

SCV000911369

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 16, 2023)

germline

clinical testing

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

SCV002532730

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Jun 22, 2021)

germline

curation

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

Citation Link

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, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

TP53 mutation analysis in chronic lymphocytic leukemia: comparison of different detection methods.

Kantorova B, Malcikova J, Smardova J, Pavlova S, Trbusek M, Tom N, Plevova K, Tichy B, Truong S, Diviskova E, Kotaskova J, Oltova A, Patten N, Brychtova Y, Doubek M, Mayer J, Pospisilova S.

Tumour Biol. 2015 May;36(5):3371-80. doi: 10.1007/s13277-014-2971-0. Epub 2014 Dec 20.

PubMed [citation]

PMID:: 25527155

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000274731.7

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

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 Color Diagnostics, LLC DBA Color Health, SCV000911369.4

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

Description

This missense variant replaces glutamine with lysine at codon 317 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that the mutant protein retains normal function (PMID 12826609, 25527155, 30224644). This variant has been reported in an individual affected with chronic lymphocytic leukemia (PMID 25527155). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 2/282868 chromosomes 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 Sema4, Sema4, SCV002532730.1

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

#	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: Oct 20, 2024

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