ClinVar Genomic variation as it relates to human health

This c.283C>T (p.Arg95*) variant in the CHEK2 gene has been reported in two patients from Norway with advanced breast cancer [PMID 18725978]. The c.283C>T (p.Arg95*) variant was subsequently detected in 12 individuals from a case control study: 4 from the control group (no cancer), 4 had prostate cancer and 4 had breast cancer [PMID 27708748]. The variant was also detected in a cohort of patients with breast cancer [PMID 21244692]. This c.283C>T creates a stop codon at amino acid position 95 of the CHEK2 protein (p.Arg95*), which is predicted to results in a loss of function of the protein. This variant has been observed in 2 heterozygous individuals in the ExAC population database (http://exac.broadinstitute.org/variant/22-29130427-G-A). It is thus interpreted as a pathogenic variant

Nonsense 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; Observed in individuals with CHEK2-related cancers (Chrisanthar et al., 2008; Le Calvez-Kelm et al., 2011; Knappskog et al., 2016; Decker et al., 2017; Raskin et al., 2017; Li et al., 2019; Petridis et al., 2019); Published functional studies demonstrate a damaging effect: absent kinase activity (Chrisanthar et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32980694, 32805687, 32923877, 29922827, 18725978, 27708748, 24763289, 24879340, 25525159, 29212164, 21244692, 27751358, 28779002, 28944238, 29752822, 29915322, 29470806, 29520813, 31263054, 31050813, 31360903, 32091409, 31447099, 32029870, 31214711)

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. The variant was found in at least one symptomatic patient and found in general population data that is consistent with pathogenicity.

This variant changes 1 nucleotide in exon 2 of the CHEK2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals affected with breast cancer (PMID: 18725978, 21244692, 27028851, 27708748, 28779002), colorectal cancer (PMID: 24506336) and prostate cancer (PMID: 27708748), as well as in several unaffected individuals (PMID: 27708748). This variant has been identified in 2/251218 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.283C>T (p.Arg95X) variant results in a premature termination codon, predicted to cause a truncated or absent CHEK2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1100delC, p.Thr367fsX15; c.1263delT, p.Ser422fsX15; c.1555C>T, p.Arg519X). One in silico tool predicts a damaging outcome for this variant. One study showed lack of dimerization of this variant with the WT Chk2 protein as well as no kinase activity (Chrisanthar_2008). This variant was found in 6/255878 control chromosomes at a frequency of 0.0000234, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284). This variant was reported in multiple patients with breast, prostate, and colorectal cancer (Knappskog_2016, Calvez-Kelm_2011, Cragun_2014), most frequently in patients of Norwegian descent . In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

The CHEK2 c.283C>T; p.Arg95Ter variant (rs587781269) is described in the literature in individuals with breast, prostate, or colorectal cancer (Chrisanthar 2008, DeRycke 2017, Knappskog 2016, Le Calvez-Kelm 2011, Li 2019, Raskin 2017, Singh 2018). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 140772). It is found in the general population with a low overall allele frequency of 0.0008% (2/251218 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Chrisanthar R et al. CHEK2 mutations affecting kinase activity together with mutations in TP53 indicate a functional pathway associated with resistance to epirubicin in primary breast cancer. PLoS One. 2008 Aug 26;3(8):e3062. DeRycke MS et al. Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. Mol Genet Genomic Med. 2017 Jul 23;5(5):553-569. Knappskog S et al. Prevalence of the CHEK2 R95* germline mutation. Hered Cancer Clin Pract. 2016 Sep 27;14:19. Le Calvez-Kelm F et al. Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res. 2011 Jan 18;13(1):R6. Li JY et al. Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. Int J Cancer. 2019 Jan 15;144(2):281-289. Raskin L et al. Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort. Oncotarget. 2017 Jun 21;8(55):93450-93463. Singh J et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat. 2018 Jul;170(1):189-196.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

The p.R95* pathogenic mutation (also known as c.283C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 283. This changes the amino acid from an arginine to a stop codon within coding exon 1. This mutation has been detected in multiple breast cancer cohorts (Chrisanthar R et al. PLoS ONE, 2008 Aug;3:e3062; Le Calvez-Kelm F et al. Breast Cancer Res, 2011 Jan;13:R6; Knappskog S et al. Hered Cancer Clin Pract, 2016 Sep;14:19; Decker B et al. J Med Genet, 2017 11;54:732-741; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Li JY et al. Int J Cancer, 2019 01;144:281-289; Petridis C et al. Cancer Epidemiol Biomarkers Prev, 2019 07;28:1162-1168; Mandelker D et al. JNCI Cancer Spectr, 2019 Jun;3:pkz027; Hata C et al. J Hum Genet, 2020 Jul;65:577-587; Chen B et al. Aging (Albany NY), 2020 02;12:3140-3155). In one case control study, this variant was reported in 8/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been detected in patients with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463) as well as prostate cancer (Knappskog S et al. Hered Cancer Clin Pract, 2016 Sep;14:19; Wu Y et al. Prostate, 2018 06;78:607-615; Mijuskovic M et al. Br J Cancer, 2018 07;119:96-104; Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). 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.

CHEK2: PVS1:Strong, PM2, PS3:Moderate, PS4:Moderate

This sequence change creates a premature translational stop signal (p.Arg95*) 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 (rs587781269, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer or prostate cancer (PMID: 18725978, 21244692, 27708748). ClinVar contains an entry for this variant (Variation ID: 140772). For these reasons, this variant has been classified as Pathogenic.

The CHEK2 c.283C>T variant is predicted to result in premature protein termination (p.Arg95*). This variant has been reported in individuals with breast, ovarian, prostate, and colorectal cancer, but has also been reported at low frequencies in unaffected individuals (Chrisanthar et al. 2008. PubMed ID: 18725978; Knappskog et al. 2016. PubMed ID: 27708748; Raskin et al. 2017. PubMed ID: 29212164, Table S2; Singh et al. 2018. PubMed ID: 29470806, Table S2; Wu et al. 2018. PubMed ID: 29520813, Table 2; Li et al. 2018. PubMed ID: 29752822, Table S4). Although found in several ancestral populations, it has been reported as potential founder variant in individuals of Norwegian ancestry (Knappskog et al. 2016. PubMed ID: 27708748). In vitro experimental studies suggests that this variant leads to loss of CHEK2 protein dimerization and kinase activity (Chrisanthar et al. 2008. PubMed ID: 18725978). This variant is reported in 2 of ~251,000 alleles in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140772/). Nonsense variants in CHEK2 are expected to be pathogenic. This variant is interpreted as pathogenic.

The CHEK2 p.Arg95X variant was identified in 10 of 21084 proband chromosomes (frequency: 0.00047) from individuals or families with breast and prostate cancer (Knappskog_2016_27708748, Le Calvez-Kelm_2011_21244692, Wu_2018_29520813). The variant was also identified in dbSNP (ID: rs587781269) as “with pathogenic allele”, ClinVar (as pathogenic by Ambry Genetics, GeneDx, Invitae, Counsyl and Mayo), Clinvitae (3x as in ClinVar), and Zhejiang Colon Cancer Database (2x in primary breast cancer). The variant was not identified in Cosmic, and MutDB databases. The variant was identified in control databases in 2 of 246164 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European (Non-Finnish) in 1 of 111644 chromosomes (freq: 0.000009), and South Asian in 1 of 30776 chromosomes (freq: 0.000032), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or European (Finnish) populations. In a study of cancer patients in Norway, two individuals affected with breast cancer were found to carry this variant; in both patients carrying the variant, these tumours were non-responsive to epirubicin therapy (Chrisanthar_2008_18725978). In addition, the p.Arg95Ter variant protein was found to be unable to form dimers with wild-type CHEK2, and the variant was totally devoid of any CHEK2 kinase activity (Chrisanthar_2008_18725978). The p.Arg95X variant leads to a premature stop codon at position 95 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease in hereditary breast and ovarian cancer 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.

Variant interpreted as Pathogenic and reported on 03-02-2017 by Lab Myriad. 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.