ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1216C>T (p.Arg406Cys) (rs587782527)

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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 RCV000131715 SCV000186753 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000587346 SCV000210986 uncertain significance not provided 2018-04-19 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1216C>T at the cDNA level, p.Arg406Cys (R406C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). Case-control studies observed this variant in three individuals with a personal history of breast or ovarian cancer, two of whom also had a family history of breast cancer, but not in healthy controls (Osorio 2004, Le Calvez-Kelm 2011, Rashid 2013). This variant, also reported as CHEK2 Arg449Cys using alternate nomenclature, has also been observed in at least one individual diagnosed with sarcoma (Ballinger 2016). 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). This variant is located in the kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Arg406Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000228975 SCV000289656 uncertain significance Familial cancer of breast 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 406 of the CHEK2 protein (p.Arg406Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587782527, ExAC 0.006%). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 14618615, 23806170, 21244692) as well as prostate cancer (PMID: 29368341). ClinVar contains an entry for this variant (Variation ID: 142533). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 RCV000228975 SCV000488796 uncertain significance Familial cancer of breast 2016-06-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515410 SCV000611449 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
Color RCV000131715 SCV000684570 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855593 SCV000698764 uncertain significance not specified 2019-03-28 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1216C>T (p.Arg406Cys) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 280054 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (6.1e-05 vs 0.00031), allowing no conclusion about variant significance. The variant, c.1216C>T has been reported in the literature in an individual with moderate risk for Breast Cancer (BrC) and/or Ovarian Cancer (OC) and in patients with BrC, OC or Prostate Cancer (Calvez-Kelm_2011, Rashid_2013, Osorio_2004, Isaacsson_2018 , Koczkowska_2018). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported by our laboratory (BRCA1 c.1326T>A, p.Cys442X; BRCA2 c.6468_6469delTC, p.Q2157fs*18), 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 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics RCV000228975 SCV000839463 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing

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