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 2018-07-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
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.
Invitae RCV000198345 SCV000254945 uncertain significance Familial cancer of breast 2019-12-30 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 observed in individual(s) 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). This variant has been reported not to substantially affect CHEK2 protein function (PMID: 30851065). 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 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
Color RCV000130733 SCV000684658 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855592 SCV000698811 likely benign not specified 2019-03-26 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.556A>C (p.Asn186His) results in a conservative amino acid change located in the Forkhead-associated (FHA) domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 277188 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (6.5e-05 vs 0.00031), allowing no conclusion about variant significance. c.556A>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Aloraifi_2015, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.130T>A, p.Cys44Ser; BRCA1 c.2359dupG, p.Glu787GlyfsX3), providing supporting evidence for a benign role. A functional study, Delimitsou_2019, performed an in vivo, yeast-based, functional assay and found the variant to act comparable to wild-type and was classified as benign. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
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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