ClinVar Miner

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

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130733 SCV000185624 likely benign Hereditary cancer-predisposing syndrome 2020-07-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study
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 2020-09-26 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 individuals with breast cancer (PMID: 26094658, 30303537) and in an individual with pleomorphic xanthoastrocytoma and meningioma (PMID: 30374176). 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; Bone osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130733 SCV000684658 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-17 criteria provided, single submitter clinical testing This missense variant replaces asparagine with histidine at codon 186 of the CHEK2 protein. this variant is also known as p.Asn229His in the literature based on an alternate transcript NM_001005735. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown the mutant protein to be functional in DNA damage response assay in yeast (PMID: 30851065). This variant has been reported in two individuals affected with breast cancer (PMID: 25186627, 26094658). It has also been identified in 19/282804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855592 SCV000698811 likely benign not specified 2020-11-24 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 6e-05 in 251420 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (6e-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 (example Aloraifi_2015, Tung_2015, Girard_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.2359dupG, p.Glu787GlyfsX3 (Tung_2015); BRCA1 c.130T>A, p.Cys44Ser, at our laboratory), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Delimitsou_2019). These results showed no damaging effect of this variant in an in-vivo, yeastbased, functional assay. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance citing overlapping literature evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant retained its classification 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356295 SCV001551423 uncertain significance Endometrial carcinoma no assertion criteria provided clinical testing The CHEK2 p.Asn186His variant was identified in 1 of 208 proband chromosomes (frequency: 0.005) from individuals or families with non-BRCA1/2 breast cancer and was not identified in 202 control chromosomes from healthy individuals (Aloraifi 2015). The variant was identified in dbSNP (ID: rs146198085) as “With Uncertain significance allele”, in ClinVar (classified with conflicting interpretations of pathogenicity: likely benign by Laboratory Corporation of America; and uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Fulgent Genetics and Color Genomics Inc), Clinvitae (4x), Cosmic (1x in a wilms tumour), and Zhejiang Colon Cancer Database (1x), but was not found in MutDB. The variant was also identified in control databases in 18 of 277188 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 3 of 24028 chromosomes (freq: 0.0001), and European Non-Finnish in 15 of 126684 chromosomes (freq: 0.0001); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Asn186 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant His to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000589669 SCV001740948 uncertain significance not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000589669 SCV001799702 uncertain significance not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000589669 SCV001806979 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000589669 SCV001906169 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000589669 SCV001955390 uncertain significance not provided no assertion criteria provided clinical testing

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