ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.444+1G>T (rs121908698)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199852 SCV000253712 pathogenic Familial cancer of breast 2019-11-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the CHEK2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs121908698, ExAC 0.001%). This variant has been observed in an individual affected with breast cancer (PMID: 18058223), and an individual affected with non-Hodgkin lymphoma (PMID: 26506619). This variant is also known as IVS2+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 126914). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 26506619). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000114770 SCV000279576 pathogenic not provided 2016-01-06 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.444+1G>T or IVS3+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 3 of the CHEK2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, previously reported as IVS2+1G>T, has been observed in association with breast cancer (Kleibl 2008) and a different substitution at the same position, c.444+1G>A, is a Polish founder variant (Cybulski 2004). Based on the current evidence, we consider this variant to be pathogenic.
Counsyl RCV000199852 SCV000677778 likely pathogenic Familial cancer of breast 2017-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV001022484 SCV001184229 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-14 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Functionally-validated splicing mutation
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague RCV000114770 SCV000148665 not provided not provided no assertion provided not provided

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