ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.556A>C (p.Asn186His) (rs146198085)

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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 RCV000130733 SCV000185624 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130733 SCV000684658 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
Counsyl RCV000198345 SCV000489187 uncertain significance Familial cancer of breast 2016-09-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515236 SCV000611456 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000589669 SCV000210966 uncertain significance not provided 2018-05-25 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.556A>C at the cDNA level, p.Asn186His (N186H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). This variant, also denoted CHEK2 685A>C (Asn229His) using alternate nomenclature, has been observed in at least two individuals with breast cancer (Aloraifi 2015, Tung 2015). CHEK2 Asn186His was observed at an allele frequency of 0.01% (3/24,028) in individuals of African ancestry in large population cohorts (Lek 2016). CHEK2 Asn186His is located in the FHA 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 Asn186His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589669 SCV000698811 likely benign not provided 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.556A>C (p.Asn186His) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution in the SMAD/Forkhead-associated domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0000659 (8/121332 control chromosomes), which is more than 2 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284), suggesting this variant is likely a benign polymorphism. In addition, this variant was found to co-occur with the pathogenic BRCA1 mutation c.130T>A (p.Cys44Ser) in an internal sample, which also indicates a benign nature of the variant. This variant has been reported in one BrC patient without strong evidence for causality. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as one of uncertain significance, without evidence for independent evaluation. To our knowledge, the variant of interest has not been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign until more information becomes available.
Invitae RCV000198345 SCV000254945 uncertain significance Familial cancer of breast 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 186 of the CHEK2 protein (p.Asn186His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs146198085, ExAC 0.02%). This variant has been reported in the literature in an individual with breast cancer (PMID: 26094658). It is referred to as c.685T>G (p.Asn229His) using a different reference transcript in the literature. ClinVar contains an entry for this variant (Variation ID: 141977). 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 disruptive, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589669 SCV000888113 uncertain significance not provided 2017-09-18 criteria provided, single submitter clinical testing

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