ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1217G>A (p.Arg406His) (rs200649225)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132141 SCV000187212 likely benign Hereditary cancer-predisposing syndrome 2017-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: No disease association in small case-control study,Intact protein function observed in appropriate functional assay(s)
Invitae RCV000215450 SCV000253479 likely benign not provided 2019-03-02 criteria provided, single submitter clinical testing
GeneDx RCV000215450 SCV000278927 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1217G>A at the cDNA level, p.Arg406His (R406H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was observed in several individuals with breast cancer (Novak 2008, Soumittra 2009, Caminsky 2016, Tung 2016) and in at least one individual with a personal history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015), but has also been observed in healthy controls (Novak 2008). In a yeast complementation assay, cells transformed with this variant demonstrated cell growth and survival comparable to wild type (Yilmaz 2014). Although this variant was observed in large population cohorts, data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). CHEK2 Arg406His is located in the kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Arg406His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000132141 SCV000902709 likely benign Hereditary cancer-predisposing syndrome 2015-10-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780184 SCV000917237 likely benign not specified 2018-07-09 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1217G>A (p.Arg406His) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 276652 control chromosomes, predominantly within the South Asian subpopulation in the gnomAD database at a frequency of 0.0017, including 1 homozygote. The frequency within South Asian control individuals in the gnomAD database is more than 5-fold above the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1217G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence by yeast complementation assays, which showed activity similar to that of WT controls (Yilmaz_2014). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations, including VUS (1x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.

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