Submissions for variant NM_007194.4(CHEK2):c.539G>A (p.Arg180His)

gnomAD frequency: 0.00006  dbSNP: rs137853009

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212427	SCV000149934	uncertain significance	not provided	2023-07-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate normal phosphorylation in response to DNA damage, but partially reduced protein expression, stability, and kinase activity when compared to wild type (Sodha et al., 2006; Desrichard et al., 2011; Delimitsou et al., 2019; Kleiblova et al., 2019); Observed in individuals with CHEK2-related and other cancers, some of whom had pathogenic variants in other genes (Sodha et al., 2002; Dong et al., 2003; Pugh et al., 2013; Pearlman et al., 2017; Penkert et al., 2018; Greville-Hetgate et al., 2020); 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; This variant is associated with the following publications: (PMID: 25629968, 18167186, 21244692, 18085035, 19782031, 15239132, 22385513, 16982735, 12454775, 12533788, 23334666, 22114986, 26787654, 15818573, 27978560, 28055978, 30851065, 30086788, 31050813, 31159747, 22419737, 32923877, 35980532, 36980535, 36983691, 33471991)
Ambry Genetics	RCV000116025	SCV000186257	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	The p.R180H variant (also known as c.539G>A), located in coding exon 3 of the CHEK2 gene, results from a G to A substitution at nucleotide position 539. The arginine at codon 180 is replaced by histidine, an amino acid with highly similar properties. This variant has been identified in individuals diagnosed with breast, prostate, and colorectal cancer (Sodha N et al. Br. J. Cancer. 2002 Dec;87:1445-8; Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Greville-Heygate SL et al. JCO Precis Oncol, 2020 May;4:). Functional analyses of the p.R180H allele have supported pathogenicity, with most studies demonstrating low or intermediate levels of functional impairment (Sodha N et al. Cancer Res. 2006 Sep;66:8966-70; Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648; Kleiblova P et al. Int. J. Cancer, 2019 10;145:1782-1797; Desrichard A et al. Breast Cancer Res. 2011 Nov;13:R119). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by silico analyses. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000206384	SCV000260730	uncertain significance	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 180 of the CHEK2 protein (p.Arg180His). This variant is present in population databases (rs137853009, gnomAD 0.03%). This missense change has been observed in individual(s) with prostate cancer, breast cancer, colorectal cancer, and neuroblastoma (PMID: 12454775, 12533788, 23334666, 27978560, 30086788, 31159747, 32923877). ClinVar contains an entry for this variant (Variation ID: 5596). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 16982735, 22114986). 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	RCV000206384	SCV000489564	uncertain significance	Familial cancer of breast	2016-10-27	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000116025	SCV000822002	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116025	SCV000902809	likely benign	Hereditary cancer-predisposing syndrome	2015-04-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780186	SCV000917240	uncertain significance	not specified	2022-10-26	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.539G>A (p.Arg180His) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain of 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 6.3e-05 in 253624 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.3e-05 vs 0.00031), allowing no conclusion about variant significance. c.539G>A has been reported in the literature in individuals affected with various types of cancers including breast cancer, prostate cancer, colorectal cancer (Desrichard_2011, Dong_2003, Pearlman_2016, Penkert_2018, Sodha_2002, van Puijenbroek_2005, Young_2016, Kleiblova_2019, Tsaousis_2019, Pereira_2022). Functional studies indicate that the variant slightly effects protein expression, stability and kinase activity as measured by activation in response to etoposide induced DNA damage (Sodha_2002). However, this data does not allow convincing conclusions about the variant effect. Co-occurrences with other pathogenic variant(s) have been reported (ATM c.5932G>T, p.Glu1978Ter; CHEK2 c.1100delC, p.Thr367fs), providing supporting evidence for a benign role (Penkert_2018 and Sodha_2002). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000206384	SCV001141368	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV000206384	SCV001424817	uncertain significance	Familial cancer of breast	2019-04-02	criteria provided, single submitter	clinical testing	The c.539G>A variant has been reported in individuals affected with breast cancer, colon cancer, prostate cancer and neuroblastoma (Sodha 2002, Dong 2003, Pugh 2013, Pearlman 2016). The c.539G>A variant has an overall allele frequency of 0.00006 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/), and is more common in African American populations (Lek 2016). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000206384	SCV001440947	uncertain significance	Familial cancer of breast	2022-12-14	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3_MOD, PM2_SUP, PP3, BP5
Sema4, Sema4	RCV000116025	SCV002537612	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-10	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116025	SCV004014932	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000206384	SCV004020200	uncertain significance	Familial cancer of breast	2023-03-09	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.
Baylor Genetics	RCV000206384	SCV004217563	uncertain significance	Familial cancer of breast	2023-09-08	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000780186	SCV004243028	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
OMIM	RCV003333686	SCV000026126	pathogenic	Malignant tumor of prostate	2003-02-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354132	SCV001548673	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Arg180His variant was identified in 6 of 1998 proband chromosomes (frequency: 0.003) from individuals or families with breast, prostate, neuroblastoma and colorectal cancer and was present in 1 of 846 control chromosomes (frequency: 0.002) from healthy individuals (Sodha 2002, Dong 2003, Pearlman 2017, Pugh 2013, Penkert 2018). The variant was identified in dbSNP (rs137853009) as “with pathogenic, uncertain significance allele”, ClinVar (classified as "uncertain significance by Invitae and 5 others, "pathogenic" by OMIM and "likely benign" by Color). The variant was identified in control databases in 18 of 277,176 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24,028 chromosomes (freq: 0.00008), Latino in 9 of 34,420 chromosomes (freq: 0.0002), European in 7 of 126,672 chromosomes (freq: 0.00006); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. In response to DNA damage, cells expressing the p.Arg180His variant resembled wild type by demonstrating normal levels of phosphorylation and proper oligomerization (Sodha 2006). In another study, a recombinant protein expressing the variant reduced kinase activity, but did not completely abolish the protein’s function (Desrichard 2011). Additionally, the p.Arg180His variant co-occurred with pathogenic variants in both the same gene (CHEK2 c.1100delC) and the ATM gene (p.Glu1978X) in breast cancer patients (Sodha 2002, Penkert 2018). The p.Arg180 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.