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

gnomAD frequency: 0.00001  dbSNP: rs369223840

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206453	SCV000259442	uncertain significance	Familial cancer of breast	2024-01-02	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 (Invitae). 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	2022-10-26	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. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	2023-06-07	criteria provided, single submitter	clinical testing	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; Reported in individuals with a personal and/or family history of breast and/or ovarian cancer, and also in unaffected controls (Kim et al., 2017; Momozawa et al., 2018); Also known as c.686A>G; p.(N229S); This variant is associated with the following publications: (PMID: 25420024, 30287823, 23911319, 26818556, 25417114, 28555940, 31398194, 19782031, 22419737, 27783279)
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	2023-06-02	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with personal and/or family history of breast cancer (PMIDs: 27783279 (2016), 33471991 (2021), see also http://databases.lovd.nl/shared/genes/CHEK2)), as well as in healthy individuals (PMIDs: 28779002 (2017), 30287823 (2018), 33471991 (2021), 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.