ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.557A>G (p.Asn186Ser)

gnomAD frequency: 0.00001  dbSNP: rs369223840
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000206453 SCV000259442 uncertain significance Familial cancer of breast 2025-01-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 186 of the CHEK2 protein (p.Asn186Ser). This variant is present in population databases (rs369223840, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 27783279). This variant is also known as c.686A>G (p.N229S). ClinVar contains an entry for this variant (Variation ID: 219529). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
Ambry Genetics RCV000219155 SCV000273004 uncertain significance Hereditary cancer-predisposing syndrome 2024-10-09 criteria provided, single submitter clinical testing The p.N186S variant (also known as c.557A>G), located in coding exon 3 of the CHEK2 gene, results from an A to G substitution at nucleotide position 557. The asparagine at codon 186 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. This variant was reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res 2023 Aug;29(16):3037-3050). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000206453 SCV000488308 uncertain significance Familial cancer of breast 2016-03-23 criteria provided, single submitter clinical testing
GeneDx RCV000481149 SCV000564872 uncertain significance not provided 2023-12-22 criteria provided, single submitter clinical testing Reported in individuals with a personal and/or family history of breast, ovarian, and other cancers, and also in unaffected control groups (PMID: 27783279, 30287823, 36243179, 33850299); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.686A>G; p.(N229S); This variant is associated with the following publications: (PMID: 25420024, 30287823, 23911319, 26818556, 25417114, 28555940, 31398194, 27783279, 19782031, 22419737, 36243179, 34482403, 33850299)
Color Diagnostics, LLC DBA Color Health RCV000219155 SCV000684659 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-21 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 186 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant (also known as p.Asn229Ser in the literature) has been reported in an individual with personal and/or family history of breast cancer (PMID: 27783279). This variant has also been identified in 8/251416 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV003447517 SCV001251950 uncertain significance Malignant tumor of breast 2023-12-10 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001818496 SCV002067638 uncertain significance not specified 2021-03-10 criteria provided, single submitter clinical testing
Mendelics RCV001818496 SCV002518093 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000206453 SCV002580774 uncertain significance Familial cancer of breast 2022-01-26 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000206453 SCV004020111 uncertain significance Familial cancer of breast 2023-03-08 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481149 SCV004221747 uncertain significance not provided 2024-02-12 criteria provided, single submitter clinical testing The CHEK2 c.557A>G (p.Asn186Ser) variant has been reported in the published literature in individuals with a personal and/or family history of breast cancer (PMID: 27783279 (2016), 33471991 (2021), see also http://databases.lovd.nl/shared/genes/CHEK2)). This variant has also been identified in reportedly healthy individuals (PMID: 28779002 (2017), 30287823 (2018), 33471991 (2021), 36243179 (2022), see also http://databases.lovd.nl/shared/genes/CHEK2)). The frequency of this variant in the general population, 0.00012 (4/34588 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics RCV000206453 SCV005058367 uncertain significance Familial cancer of breast 2024-02-17 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005025330 SCV005663131 uncertain significance Li-Fraumeni syndrome 2; Bone osteosarcoma; Familial prostate cancer 2024-05-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV005361169 SCV005912040 uncertain significance Li-Fraumeni syndrome 2 2021-11-09 criteria provided, single submitter clinical testing

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