Submissions for variant NM_007194.4(CHEK2):c.1604G>A (p.Arg535His)

gnomAD frequency: 0.00027  dbSNP: rs544216926

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212482	SCV000149917	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing	Published functional studies are inconclusive: intermediate response to DNA damage (Delimitsou et al., 2019); Observed in individuals with breast cancer or sarcoma (Ballinger et al., 2016; Fonfria et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.1733G>A p.R578H; This variant is associated with the following publications: (PMID: 24879340, 36315097, 27498913, 30851065, 34204722, 33309985, 30287823)
Ambry Genetics	RCV000116008	SCV000213783	likely benign	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000412260	SCV000489079	uncertain significance	Familial cancer of breast	2016-08-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412260	SCV000561008	likely benign	Familial cancer of breast	2024-12-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116008	SCV000910857	likely benign	Hereditary cancer-predisposing syndrome	2017-06-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818284	SCV002071401	uncertain significance	not specified	2021-11-22	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in individuals with CHEK2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.20% in the South Asian subpopulation (dbSNP rs544216926). The p.Arg535His change affects a poorly conserved amino acid residue located in a domain of the CHEK2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg535His substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Arg535His change remains unknown at this time.
Sema4, Sema4	RCV000116008	SCV002537404	likely benign	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818284	SCV002548438	likely benign	not specified	2024-10-28	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1604G>A (p.Arg535His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 233674 control chromosomes, predominantly at a frequency of 0.002 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031). The variant, c.1604G>A, has been reported in the literature in individuals affected with breast cancer and other tumor phenotypes, but was also found in several controls (e.g. Ow_2014, Fujita_2020, Fonfria_2021, Dorling_2021, Stolarova_2023). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Publications also reported experimental evidence evaluating an impact on protein function, and in a yeast-based functional assay, the variant was reported to have intermediate function (Delimitsou_2019), while in a later study, using a human cell-line the variant had kinase activity similar to the WT (Stolarova_2023). The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 33309985, 34204722, 24879340, 33471991, 37449874). ClinVar contains an entry for this variant (Variation ID: 128067). Based on the evidence outlined above, the variant was classified as likely benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116008	SCV004014943	benign	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412260	SCV004020217	likely benign	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212482	SCV004221736	likely benign	not provided	2023-07-14	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818284	SCV004243012	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000412260	SCV005042910	uncertain significance	Familial cancer of breast		criteria provided, single submitter	clinical testing	The missense c.1604G>Ap.Arg535His variant in CHEK2 gene has been reported previously in individuals affected with cancer Fonfria M, et al., 2021. Functional studies show that the variant has intermediate function Delimitsou A, et al., 2019. The p.Arg535His variant has been reported with allele frequency of 0.03% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Benign / Uncertain Significance. The amino acid change p.Arg535His in CHEK2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 535 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212482	SCV002034908	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000212482	SCV002035687	likely benign	not provided		no assertion criteria provided	clinical testing