NM_007194.4(CHEK2):c.1525C>T (p.Pro509Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Mar 5, 2024
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:: RCV000116004.21

Allele description [Variation Report for NM_007194.4(CHEK2):c.1525C>T (p.Pro509Ser)]

NM_007194.4(CHEK2):c.1525C>T (p.Pro509Ser)

Gene:

CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q12.1

Genomic location:

Preferred name:

NM_007194.4(CHEK2):c.1525C>T (p.Pro509Ser)

Other names:

p.P509S:CCC>TCC

HGVS:

NC_000022.11:g.28689152G>A
NG_008150.2:g.57715C>T
NM_001005735.2:c.1654C>T
NM_001257387.2:c.862C>T
NM_001349956.2:c.1324C>T
NM_007194.4:c.1525C>TMANE SELECT
NM_145862.2:c.1438C>T
NP_001005735.1:p.Pro552Ser
NP_001244316.1:p.Pro288Ser
NP_001336885.1:p.Pro442Ser
NP_009125.1:p.Pro509Ser
NP_665861.1:p.Pro480Ser
LRG_302t1:c.1525C>T
LRG_302:g.57715C>T
LRG_302p1:p.Pro509Ser
NC_000022.10:g.29085140G>A
NM_007194.3:c.1525C>T
p.P509S

Protein change:

P288S

Links:

dbSNP: rs587780179

NCBI 1000 Genomes Browser:

rs587780179

Molecular consequence:

NM_001005735.2:c.1654C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001257387.2:c.862C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.1324C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.1525C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.1438C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; 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
SCV000186790	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Mar 5, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 29522266, 30851065, 31050813, 31409080, 32546565, 34903604 Citation Link,
SCV000902768	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Mar 3, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002537390	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Nov 16, 2021)	germline	curation	PubMed (9) [See all records that cite these PMIDs] 31050813, 18571837, 25980754, 33471991, 29522266, 28051113, 32546565, 32906215, 30851065 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186790

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Mar 5, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV000902768

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Mar 3, 2016)

germline

clinical testing

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

SCV002537390

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Nov 16, 2021)

germline

curation

PubMed (9)
[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

Germline CHEK2 Gene Mutations in Hereditary Breast Cancer Predisposition - Mutation Types and their Biological and Clinical Relevance.

Kleiblová P, Stolařová L, Křížová K, Lhota F, Hojný J, Zemánková P, Havránek O, Vočka M, Černá M, Lhotová K, Borecká M, Janatová M, Soukupová J, Ševčík J, Zimovjanová M, Kotlas J, Panczak A, Veselá K, Červenková J, Schneiderová M, Burócziová M, Burdová K, et al.

Klin Onkol. 2019 Summer;32(Supplementum2):36-50. doi: 10.14735/amko2019S36.

PubMed [citation]

PMID:: 31409080

Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk.

Boonen RACM, Wiegant WW, Celosse N, Vroling B, Heijl S, Kote-Jarai Z, Mijuskovic M, Cristea S, Solleveld-Westerink N, van Wezel T, Beerenwinkel N, Eeles R, Devilee P, Vreeswijk MPG, Marra G, van Attikum H.

Cancer Res. 2022 Feb 15;82(4):615-631. doi: 10.1158/0008-5472.CAN-21-1845.

PubMed [citation]

PMID:: 34903604
PMCID:: PMC9359737

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV000186790.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

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, SCV000902768.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002537390.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (9)

#	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: Jul 13, 2025

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