ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.417C>A (p.Tyr139Ter) (rs200917541)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507030 SCV000601167 pathogenic not provided 2017-06-28 criteria provided, single submitter clinical testing
Invitae RCV000541871 SCV000633182 pathogenic Familial cancer of breast 2020-08-26 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CHEK2-related disease. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000572280 SCV000669284 pathogenic Hereditary cancer-predisposing syndrome 2020-09-22 criteria provided, single submitter clinical testing 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.
Fulgent Genetics,Fulgent Genetics RCV000763476 SCV000894258 pathogenic Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000572280 SCV001339370 pathogenic Hereditary cancer-predisposing syndrome 2019-09-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001375597 SCV001572499 pathogenic Hereditary breast and ovarian cancer syndrome 2021-04-04 criteria provided, single submitter clinical testing 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.

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