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NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met) AND CHEK2-related disorder

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Aug 20, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV004528804.2

Allele description [Variation Report for NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met)]

NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met)

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.1427C>T (p.Thr476Met)
Other names:
p.T476M:ACG>ATG
HGVS:
  • NC_000022.11:g.28694066G>A
  • NG_008150.2:g.52801C>T
  • NM_001005735.2:c.1556C>T
  • NM_001257387.2:c.764C>T
  • NM_001349956.2:c.1226C>T
  • NM_007194.4:c.1427C>TMANE SELECT
  • NM_145862.2:c.1340C>T
  • NP_001005735.1:p.Thr519Met
  • NP_001244316.1:p.Thr255Met
  • NP_001336885.1:p.Thr409Met
  • NP_009125.1:p.Thr476Met
  • NP_665861.1:p.Thr447Met
  • LRG_302t1:c.1427C>T
  • LRG_302:g.52801C>T
  • LRG_302p1:p.Thr476Met
  • NC_000022.10:g.29090054G>A
  • NG_008150.1:g.52769C>T
  • NM_001005735.1:c.1556C>T
  • NM_007194.3:c.1427C>T
  • p.T476M
Protein change:
T255M
Links:
dbSNP: rs142763740
NCBI 1000 Genomes Browser:
rs142763740
Molecular consequence:
  • NM_001005735.2:c.1556C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001257387.2:c.764C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001349956.2:c.1226C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007194.4:c.1427C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_145862.2:c.1340C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
CHEK2-related disorder
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000806869PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Likely pathogenic
(Aug 20, 2024) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV000806869.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The CHEK2 c.1427C>T variant is predicted to result in the amino acid substitution p.Thr476Met. This variant has been reported in multiple individuals with breast cancer, with a recent study reporting an odds ratio of 1.35 (95% CI=1.03-1.77, P-value=0.03) (Table S1, Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Desrichard et al. 2011. PubMed ID: 22114986; Roeb et al. 2012. PubMed ID: 22419737; Angelova et al. 2012. PubMed ID: 22862163; Table S1, Susswein et al. 2016. PubMed ID: 26681312; Schubert et al. 2019. PubMed ID: 30426508; Lerner-Ellis et al. 2020. PubMed ID: 31784482; Figure 2, Bychkovsky et al. 2022. PubMed ID: 36136322). This variant has also been reported in individuals with ovarian cancer, prostate cancer, pancreatic cancer, and colorectal cancer (Table S1, Hu et al. 2016. PubMed ID: 26483394; Table S1, Susswein et al. 2016. PubMed ID: 26681312; Table 1, Isaacsson Velho et al. 2018. PubMed ID: 29368341; Table 1, Young et al. 2018. PubMed ID: 29945567; Table S4, Bertelsen et al. 2019. PubMed ID: 31263571; Table S3, Arvai et al. 2019. PubMed ID: 31341520). In vitro and in vivo experimental studies suggest this variant results in reduced or absent kinase activity and DNA damage response (Desrichard et al. 2011. PubMed ID: 22114986; Table 1, Roeb et al. 2012. PubMed ID: 22419737; Figure 1, Kleiblova et al. 2019. PubMed ID: 31050813). An additional functional study using protein expression in yeast found that his variant results in semi-functional kinase activity (Delimitsou et al. 2019. PubMed ID: 30851065). In the gnomAD public population database this variant has been reported in up to ~0.05% of alleles in a subpopulation and has conflicting interpretations of uncertain, risk allele, and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128060/). Taken together, we interpret c.1427C>T (p.Thr476Met) as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 10, 2024