ClinVar Genomic variation as it relates to human health

Variant summary: CHEK2 c.417C>A (p.Tyr139X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251288 control chromosomes. c.417C>A has been reported in the literature in multiple individuals affected with breast cancer (example, Sun_2017) and co-segregating with papillary thyroid cancer in at-least one large family (Zhao_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced p53 phosphorylation and decreased p53 protein level (Zho_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant changes 1 nucleotide in exon 3 of the CHEK2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

This nonsense variant 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 and papillary thyroid cancer (PMID: 32318955 (2020), 32041497 (2020), 28724667 (2017)). Based on the available information, this variant is classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Tyr139*) 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: 28724667, 31650731). This variant is also known as c.546C>A (p.Tyr182*). ClinVar contains an entry for this variant (Variation ID: 439092). For these reasons, this variant has been classified as Pathogenic.

The p.Y139* pathogenic mutation (also known as c.417C>A), located in coding exon 2 of the CHEK2 gene, results from a C to A substitution at nucleotide position 417. This changes the amino acid from a tyrosine to a stop codon within coding exon 2. This alteration was detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing. (Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119). This alteration was also identified in a family with papillary thyroid cancer (Zhao Y et al. Thyroid, 2020 06;30:924-930). 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.

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