ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1037G>A (p.Arg346His)

gnomAD frequency: 0.00001  dbSNP: rs730881688
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656833 SCV000210980 likely pathogenic not provided 2023-05-23 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: impaired auto-phosphorylation, reduced/absent kinase activity, and defective DNA-damage response in yeast and cell-based assays (Delimitsou et al., 2019; Kleiblova et al., 2019; Boonen et al., 2021); Identified in individuals with personal and/or family history of breast cancer (Le Calvez-Kelm et al., 2011; Hauke et al., 2018; Kleiblova et al., 2019; Boonen et al., 2021); 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: 27071721, 27294619, 31056747, 26424751, 26787654, 21244692, 28188106, 27191893, 29522266, 30851065, 31050813, 22419737, 19782031, 34903604, 33471991, 31206626, 26822949)
Ambry Genetics RCV000160430 SCV000215737 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-11 criteria provided, single submitter clinical testing The p.R346H variant (also known as c.1037G>A), located in coding exon 9 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1037. The arginine at codon 346 is replaced by histidine, an amino acid with highly similar properties. In one large study, this variant was detected in conjunction with another CHEK2 alteration (p.E239K) in 1/1303 female breast cancer cases and 0/1109 cancer-free controls (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13(1):R6). In another large study, this variant was reported in 4/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Several other studies have reported this alteration in individuals suspected to be affected with hereditary breast cancer (Young EL et al. J Med Genet, 2016 06;53:366-76; Hauke J et al. Cancer Med, 2018 04;7:1349-1358). Functional analyses for this alteration have reported conflicting results (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648; Kleiblova P. Int J Cancer. 2019 10;145(7):1782-1797; Boonen RACM et al. Cancer Res, 2022 02;82:615-631). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000203780 SCV000260748 uncertain significance Familial cancer of breast 2024-01-24 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 346 of the CHEK2 protein (p.Arg346His). This variant is present in population databases (rs730881688, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 21244692, 26822949, 31050813, 34326862). ClinVar contains an entry for this variant (Variation ID: 182431). 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. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 30851065, 31050813). 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 RCV000160430 SCV000684551 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-11 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 346 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown a deleterious effect on protein function in CHEK2 kinase activity studies (PMID 31050813, 34903604) and in a yeast-based DNA damage repair assay (PMID 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 21244692, 26822949, 29522266, 31050813, 33471991) and prostate cancer in the literature (PMID: 31214711). This variant has been identified in 3/282644 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the available evidence indicates that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl RCV000203780 SCV000785264 uncertain significance Familial cancer of breast 2017-06-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656833 SCV000889322 uncertain significance not provided 2022-08-30 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.000023 (3/129024 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 21244692 (2011), 31050813 (2019)) and in breast cancer cases and controls in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). In addition, this variant was demonstrated to have a damaging effect on CHEK2 protein function in functional analyses (PMID: 30851065 (2019) and 34903604 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844056 SCV002103838 uncertain significance not specified 2023-12-18 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1037G>A (p.Arg346His) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719); Serine/threonine-protein kinase, active site (IPR008271) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-06 in 260390 control chromosomes (gnomAD, publications). c.1037G>A has been reported in the literature in individuals affected with Breast And Ovarian Cancer or Bilary tract cancer (examples: Okawa_2023, deOliveira_2021, Dorling_2021, Kleiblova_2019, Lhota_2016, Le Calvez-Kelm_2011), but the variant was also transmitted to unaffected individuals within a family, albeit the age of the unaffected individuals with the variant was early 40s (Kleiblova_2019). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function: in vitro assays showed the variant protein had reduced ability to phosphorylate target substrate (Kleiblova_2019), and a functional yeast assay using a DNA repair deficient yeast strain showed the variant protein was incapable of rescuing cell growth and proliferation following MMS induced DNA damage (Delimitsou_2019). The most pronounced variant effect results in <10% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 33471991, 31050813, 21244692, 26822949, 36243179, 35534704). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Sema4, Sema4 RCV000160430 SCV002537018 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-09 criteria provided, single submitter curation
Baylor Genetics RCV000203780 SCV004217606 uncertain significance Familial cancer of breast 2023-08-05 criteria provided, single submitter clinical testing
GenomeConnect - Invitae Patient Insights Network RCV001535789 SCV001749948 not provided CHEK2-Related Cancer Susceptibility no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 12-21-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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