NM_007194.4(CHEK2):c.104C>G (p.Ser35Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 14, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000166389.8

Allele description [Variation Report for NM_007194.4(CHEK2):c.104C>G (p.Ser35Cys)]

NM_007194.4(CHEK2):c.104C>G (p.Ser35Cys)

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.104C>G (p.Ser35Cys)

HGVS:

NC_000022.11:g.28734618G>C
NG_008150.2:g.12249C>G
NM_001005735.2:c.104C>G
NM_001257387.2:c.-674C>G
NM_001349956.2:c.104C>G
NM_007194.4:c.104C>GMANE SELECT
NM_145862.2:c.104C>G
NP_001005735.1:p.Ser35Cys
NP_001336885.1:p.Ser35Cys
NP_009125.1:p.Ser35Cys
NP_665861.1:p.Ser35Cys
LRG_302t1:c.104C>G
LRG_302:g.12249C>G
LRG_302p1:p.Ser35Cys
NC_000022.10:g.29130606G>C
NG_008150.1:g.12217C>G
NM_007194.3:c.104C>G
p.S35C

Protein change:

S35C

Links:

dbSNP: rs786203185

NCBI 1000 Genomes Browser:

rs786203185

Molecular consequence:

NM_001257387.2:c.-674C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.104C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.104C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.104C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.104C>G - 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
SCV000217181	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28779002, 37449874 Citation Link,
SCV001339597	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 8, 2019)	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

SCV000217181

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 14, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001339597

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 8, 2019)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.

Decker B, Allen J, Luccarini C, Pooley KA, Shah M, Bolla MK, Wang Q, Ahmed S, Baynes C, Conroy DM, Brown J, Luben R, Ostrander EA, Pharoah PD, Dunning AM, Easton DF.

J Med Genet. 2017 Nov;54(11):732-741. doi: 10.1136/jmedgenet-2017-104588. Epub 2017 Aug 4.

PubMed [citation]

PMID:: 28779002
PMCID:: PMC5740532

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.

Stolarova L, Kleiblova P, Zemankova P, Stastna B, Janatova M, Soukupova J, Achatz MI, Ambrosone C, Apostolou P, Arun BK, Auer P, Barnard M, Bertelsen B; Biobank Japan., Blok MJ, Boddicker N, Brunet J, Burnside ES, Calvello M, Campbell I, Chan SH, Chen F, et al.

Clin Cancer Res. 2023 Aug 15;29(16):3037-3050. doi: 10.1158/1078-0432.CCR-23-0212.

PubMed [citation]

PMID:: 37449874
PMCID:: PMC10425727

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000217181.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.S35C variant (also known as c.104C>G), located in coding exon 1 of the CHEK2 gene, results from a C to G substitution at nucleotide position 104. The serine at codon 35 is replaced by cysteine, an amino acid with dissimilar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This alteration was reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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, SCV001339597.2

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

Description

This missense variant replaces serine with cysteine at codon 35 of the CHEK2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant 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). 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: Oct 20, 2024

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