ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.539G>A (p.Arg180His) (rs137853009)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116025 SCV000186257 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Color RCV000116025 SCV000902809 likely benign Hereditary cancer-predisposing syndrome 2015-04-23 criteria provided, single submitter clinical testing
Counsyl RCV000206384 SCV000489564 uncertain significance Familial cancer of breast 2016-10-27 criteria provided, single submitter clinical testing
GeneDx RCV000212427 SCV000149934 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.539G>A at the cDNA level, p.Arg180His (R180H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been observed in breast, colon, prostate, and neuroblastoma cancer cases including an individual with bilateral breast cancer who also carried the common CHEK2 pathogenic variant, 1100delC (Sodha 2002, Dong 2003, Pugh 2013, Pearlman 2016). Functional studies demonstrated somewhat reduced protein expression, stability, and kinase activity when compared to wild type, but normal phosphorylation in response to DNA damage was also demonstrated (Sodha 2006, Desrichard 2011). CHEK2 Arg180His was observed at an allele frequency of 0.00963% (1/10386) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Arg180His occurs at a position that is conserved across species and is within the FHA domain (Roeb 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CHEK2 Arg180His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000116025 SCV000822002 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780186 SCV000917240 uncertain significance not specified 2018-08-27 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 6.8e-05 in 279394 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (6.8e-05 vs 0.00031), allowing no conclusion about variant significance. c.539G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Desrichard_2011, Dong_2003, Pearlman_2016, Penkert_2018, Sodha_2002, van Puijenbroek_2005, Young_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (ATM, p.Glu1978X; CHEK2 c.1100delC), providing supporting evidence for a benign role. 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. Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000206384 SCV000260730 uncertain significance Familial cancer of breast 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 180 of the CHEK2 protein (p.Arg180His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs137853009, ExAC 0.01%). This variant has been reported in individuals with prostate cancer, breast cancer, colorectal cancer, and neuroblastoma (PMID: 12533788, 12454775, 27978560, 23334666, 30086788). ClinVar contains an entry for this variant (Variation ID: 5596). Experimental studies have shown that this variant results in slightly reduced expression, stability, and kinase activity (PMID: 16982735, 22114986), but resembles wild-type CHEK2 protein in response to DNA damage (PMID: 16982735). The clinical significance of these results is not known. 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.
OMIM RCV000005944 SCV000026126 pathogenic Prostate cancer, somatic 2003-02-01 no assertion criteria provided literature only

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