ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.755G>A (p.Ser252Asn) (rs587781379)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129204 SCV000183949 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000214585 SCV000279244 uncertain significance not provided 2018-06-07 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.755G>A at the cDNA level, p.Ser252Asn (S252N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported in a tumor sample from an individual with neuroblastoma (Padovan-Merhar 2016). CHEK2 Ser252Asn was observed at an allele frequency of 0.1% (18/18,864) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the kinase domain (Cai 2009, Roeb 2012). In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether CHEK2 Ser252Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227256 SCV000289704 uncertain significance Familial cancer of breast 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 252 of the CHEK2 protein (p.Ser252Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs587781379, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals with breast cancer but was also observed in unaffected controls (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 140932). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000227256 SCV000488892 uncertain significance Familial cancer of breast 2016-07-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765620 SCV000896945 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000129204 SCV000903078 likely benign Hereditary cancer-predisposing syndrome 2016-06-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030685 SCV001193561 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV001201286 SCV001372405 likely benign not specified 2020-06-30 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.755G>A (p.Ser252Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 298804 control chromosomes, predominantly at a frequency of 0.00087 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.755G>A has been reported in the literature in individuals affected with pancreatic cancer, breast cancer, or Esophageal squamous cell carcinoma (Ohmoto_2018, Momozawa_2018, Deng_2019, Chen_2019). A large case-control study in Japanese patients with breast cancer showed that odds ratio of this variant is 1.4 (95%CI=0.6-3.1), suggesting that this variant is unlikely to associate with the disease. Co-occurrence with a pathogenic variant has been reported (TP53 c.743G>A , p.Arg248Gln), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=6). Based on the evidence outlined above, the variant was classified as likely benign.

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