ClinVar Genomic variation as it relates to human health

The CHEK2 c.1263del (p.Ser422ValfsTer15) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has been reported in individuals with breast, colon, prostate, bladder, and urethral cancer (PS4; PMID: 21244692, 24556621, 26534844, 26681312, 27273131, 33803639). This variant has a maximum subpopulation frequency of 0.0086% in gnomAD v2.1.1 (https:// gnomad.broadinstitute.org/). Other truncating variants in exon 12 have been reported in individuals with CHEK2-associated cancers and are known to be pathogenic (PM5_supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM5_supporting.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as c.1392delT (p.Ser465ValfsX15); This variant is associated with the following publications: (PMID: 25431674, 24113346, 28779002, 29961768, 29625052, 21244692, 26681312, 24556621, 27273131, 27751358, 26787654, 28152038, 26534844, 29287968, 29520813, 29909963, 24763289, 30676620, 31263054, 31447099, 32832836)

This sequence change creates a premature translational stop signal (p.Ser422Valfs*15) 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 present in population databases (rs587780174, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast, prostate, bladder, colon and urethral cancer (PMID: 21244692, 24113346, 24556621, 26681312). ClinVar contains an entry for this variant (Variation ID: 128053). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

This variant deletes 1 nucleotide in exon 12 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast, bladder, colon, hematological, prostate and urethral cancer (PMID: 21244692, 24556621, 26534844, 26681312, 27273131, 33803639). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 25/60466 cases and 5/53461 unaffected controls (OR=4.422 (95%CI 1.693 to 11.552)) (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000325). This variant has been identified in 13/281654 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Variant summary: The CHEK2 c.1263delT (p.Ser422Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent CHEK2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is expected to truncate protein kinase domain. Truncations downstream of this position have been classified as pathogenic/likely pathogenic by our laboratory and others (e.g. p.Arg519X, c.1434delA, etc.). This variant was found in 6/117456 control chromosomes at a frequency of 0.0000511, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). This variant has been reported in multiple cancer patients including breast and prostate cancer and is classified as pathogenic in literature and by multiple clinical diagnostic laboratories/reputable databases. Taken together, this variant is classified as Pathogenic.

The CHEK2 c.1263delT (p.Ser422ValfsTer15) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ser422ValfsTer15 variant has been reported in at least six studies in at least 25 individuals undergoing hereditary cancer testing or diagnosed with various cancer types (La Calvez-Kelm et al. 2011; Leongamornlert et al. 2014; Mauer et al. 2014; Susswein et al. 2015; Byers et al. 2016; Leedom et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00010 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of frameshift variants, the p.Ser422ValfsTer15 variant is classified as likely pathogenic for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

DNA sequence analysis of the CHEK2 gene demonstrated a one base pair deletion in exon 12, c.1263del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon fourteen amino acids downstream of the mutation, p.Ser422Valfs*15. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CHEK2 protein with potentially abnormal function. This pathogenic sequence change has previously been described in patients with CHEK2-related cancers (PMIDs: 21244692, 24113346, 24556621, 26681312).

PVS1, PS4_STR

PVS1, PS4

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

This frameshift variant alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 27273131 (2016), 26534844 (2016), 21244692 (2011)) and prostate cancer (PMID: 24556621 (2014)). Based on the available information, this variant is classified as pathogenic.

The c.1263delT pathogenic mutation, located in coding exon 11 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1263, causing a translational frameshift with a predicted alternate stop codon (p.S422Vfs*15). This mutation has been reported in individuals with multiple cancer types including female breast, male breast, prostate, urethral, bladder, renal, pancreatic, colon, and sarcoma (Le Calvez-Kelm F et al. Breast Cancer Res, 2011 Jan;13:R6; Leongamornlert D et al. Br. J. Cancer, 2014 Mar;110:1663-72; Mauer CB et al. Genet. Med., 2014 May;16:407-12; Byers H et al. Eur J Hum Genet, 2016 11;24:1591-1597; Susswein LR et al. Genet Med, 2016 08;18:823-32; Leedom TP et al. Cancer Genet, 2016 09;209:403-407; AlDubayan SH et al. JAMA Oncol, 2019 Apr;5:514-522; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Smith PS et al. Genes Chromosomes Cancer, 2021 01;60:5-16; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In one study, this variant was reported in 25/60,466 breast cancer cases as well as 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.

Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.

The CHEK2 p.Ser422ValfsX15 variant was identified in 22 of 115016 proband chromosomes (frequency: 0.0002) from individuals or families with breast, prostate, and other types of cancer (Byers 2016, Calvez-Kelm 2011, Leedom 2016, Leongamornlert 2014, Mauer 2014, Susswein 2016). The variant was also identified in the following databases: dbSNP (ID: rs587780174) as "With Pathogenic allele", ClinVar (4x pathogenic), and Clinvitae (3x pathogenic). The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was also not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In a study by Leongamornlert (2014), this variant was found to segregate with 2 of 3 affected family members with prostate cancer. The c.1263delT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 422 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

The CHEK2 c.1263delT variant is predicted to result in a frameshift and premature protein termination (p.Ser422Valfs*15). This variant has been reported in multiple individuals with CHEK2-related cancers (Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Leongamornlert et al. 2014. PubMed ID: 24556621; Susswein et al. 2016. PubMed ID: 26681312; Decker et al. 2017. PubMed ID: 28779002; Whitworth et al 2018. PubMed ID: 29909963; Yurgelun et al 2019. PubMed ID: 29961768). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12805). Frameshift variants in CHEK2 are expected to be pathogenic. This variant is interpreted as pathogenic.

Variant interpreted as Pathogenic and reported on 10-21-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Variant interpreted as Pathogenic and reported on 04-28-2017 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.