NM_007194.4(CHEK2):c.444+2T>C AND Hereditary cancer-predisposing syndrome

Clinical significance:Likely pathogenic (Last evaluated: Apr 6, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_007194.4(CHEK2):c.444+2T>C]


CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000022.11:g.28725241A>G
  • NG_008150.1:g.21594T>C
  • NG_008150.2:g.21626T>C
  • NM_001005735.2:c.573+2T>C
  • NM_001257387.2:c.-334+2T>C
  • NM_001349956.2:c.444+2T>C
  • NM_007194.4:c.444+2T>CMANE SELECT
  • NM_145862.2:c.444+2T>C
  • LRG_302t1:c.444+2T>C
  • LRG_302:g.21626T>C
  • NC_000022.10:g.29121229A>G
  • NM_007194.3:c.444+2T>C
dbSNP: rs560596101
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001005735.2:c.573+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001257387.2:c.-334+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001349956.2:c.444+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_007194.4:c.444+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_145862.2:c.444+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]


Hereditary cancer-predisposing syndrome
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000661735Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Apr 6, 2016)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Details of each submission

From Ambry Genetics, SCV000661735.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided


The c.444+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 2 in the CHEK2 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 130000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Sep 24, 2021

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