ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.405del (p.Lys135fs)

dbSNP: rs730881699
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160449 SCV000211011 pathogenic not provided 2016-12-02 criteria provided, single submitter clinical testing This deletion of one nucleotide is denoted CHEK2 c.405delA at the cDNA level and p.Lys135AsnfsX26 (K135NfsX26) at the protein level. The normal sequence, with the base that is deleted in brackets, is ATAA[delA]TACC. The deletion causes a frameshift, which changes a Lysine to an Asparagine at codon 135, and creates a premature stop codon at position 26 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. CHEK2 c.405delA has been observed in an individual diagnosed with breast cancer prior to the age of 45 (Le Calvez-Kelm 2011). Based on currently available information, we consider this variant to be pathogenic.
Invitae RCV000206058 SCV000259929 pathogenic Familial cancer of breast 2024-01-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys135Asnfs*26) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21244692). ClinVar contains an entry for this variant (Variation ID: 182449). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000567447 SCV000666372 pathogenic Hereditary cancer-predisposing syndrome 2022-08-10 criteria provided, single submitter clinical testing The c.405delA pathogenic mutation, located in coding exon 2 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 405, causing a translational frameshift with a predicted alternate stop codon (p.K135Nfs*26). This mutation has been observed in multiple families with breast cancer (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6; Susswein LR et al. Genet Med. 2016 Aug;18(8):823-32). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc. RCV000206058 SCV004043510 pathogenic Familial cancer of breast 2023-06-23 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics RCV000206058 SCV004217723 pathogenic Familial cancer of breast 2022-11-01 criteria provided, single submitter clinical testing

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