ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.953G>A (p.Arg318His)

gnomAD frequency: 0.00003  dbSNP: rs143611747
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131968 SCV000187026 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-05 criteria provided, single submitter clinical testing The p.R318H variant (also known as c.953G>A), located in coding exon 8 of the CHEK2 gene, results from a G to A substitution at nucleotide position 953. The arginine at codon 318 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in an individual diagnosed with early-onset prostate cancer (<59 years of age); authors note that this finding is likely a germline mutation, but could represent an early somatic event (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72(2):270-80). This alteration has been identified in multiple breast cancer cohorts as well as in controls (Shirts BH et al. Genet Med. 2016 10;18:974-81; Girard E et al. Int J Cancer. 2019 04;144:1962-1974; Dorling et al. N Engl J Med. 2021 02;384:428-439; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This alteration was also seen in 0/732 breast cancer patients, 1/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). In a yeast in vivo study, p.R318H resulted in an intermediate response to DNA damage compared to wild-type (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21(12):2738-44). This amino acid position is not well 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.
GeneDx RCV000656832 SCV000210978 uncertain significance not provided 2023-08-29 criteria provided, single submitter clinical testing Published functional studies are inconclusive: intermediate response to DNA damage (Roeb et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26845104, 24728327, 12533788, 29872864, 28580595, 30303537, 35402282, 22419737, 19782031, 34933735, 33471991, 32658311, 35264596)
Invitae RCV000460267 SCV000550481 uncertain significance Familial cancer of breast 2024-01-20 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 318 of the CHEK2 protein (p.Arg318His). This variant is present in population databases (rs143611747, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 22419737, 26845104, 28580595, 34933735, 35264596). This variant is also known as Arg361His. ClinVar contains an entry for this variant (Variation ID: 133890). 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 have shown that this missense change affects CHEK2 function (PMID: 22419737). 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.
Color Diagnostics, LLC DBA Color Health RCV000131968 SCV000689750 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-07 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 318 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown the mutant protein to exhibit an intermediate functional deficit in a DNA damage repair assay in yeast (PMID: 22419737). This variant has been reported in individuals affected with familial breast cancer (PMID 22419737, 26845104, 28580595), but has also been found in healthy cohorts (PMID 24728327, 30303537, https://whi.color.com/variant/22-29095881-C-T). In a large international case-control study, this variant was reported in 13/60466 breast cancer cases and 5/53461 controls (OR=2.299, 95%CI 0.82 to 6.449, p-value=0.155; PMID: 33471991). This variant has been identified in 13/282864 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.
Mendelics RCV000460267 SCV000839473 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120557 SCV000917241 uncertain significance not specified 2020-08-07 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.953G>A (p.Arg318His) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 256088 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer Syndrome (5.5e-05 vs 0.00031), allowing no conclusion about variant significance. The variant has been reported in the literature in association with familial breast cancer and prostate cancer (Roeb_2012, Dong_2003, Haiman_2013, Shirts_2016, Xie_2018) and an in vitro functional assay demonstrated an intermediate level of DNA damage repair in yeast cells (Roeb_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Six other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Division of Medical Genetics, University of Washington RCV000460267 SCV001424814 uncertain significance Familial cancer of breast 2019-05-06 criteria provided, single submitter clinical testing The c.953G>A variant has been reported in individuals with familial breast cancer (Roeb 2012, Shirts 2016). The c.953G>A variant has an overall allele frequency of 0.00004 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.
CeGaT Center for Human Genetics Tuebingen RCV000656832 SCV001501838 uncertain significance not provided 2020-10-01 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000131968 SCV002537658 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-08 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002498557 SCV002781954 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer 2021-07-14 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003149829 SCV003838125 uncertain significance Breast and/or ovarian cancer 2022-05-30 criteria provided, single submitter clinical testing
Baylor Genetics RCV000460267 SCV004217487 uncertain significance Familial cancer of breast 2023-10-22 criteria provided, single submitter clinical testing
ITMI RCV000120557 SCV000084711 not provided not specified 2013-09-19 no assertion provided reference population

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