ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.707T>C (p.Leu236Pro)

gnomAD frequency: 0.00003  dbSNP: rs587782471
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131577 SCV000186585 likely pathogenic Hereditary cancer-predisposing syndrome 2023-06-05 criteria provided, single submitter clinical testing The p.L236P variant (also known as c.707T>C), located in coding exon 5 of the CHEK2 gene, results from a T to C substitution at nucleotide position 707. The leucine at codon 236 is replaced by proline, an amino acid with similar properties. This alteration was non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 May;40:631-648). This alteration was also observed with a statistically increased odds ratio in a cohort of Hispanic breast cancer patients compared to general population control carriers (Weitzel JN et al. Cancer. 2019 Aug;125:2829-2836). Additionally, this variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). Based on internal structural assessment, this alteration disrupts the fold of the N-lobe of the kinase domain, near the ATP-binding site (Lountos GT et al. J. Struct. Biol. 2011 Dec;176:292-301). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000586622 SCV000210971 likely pathogenic not provided 2023-06-02 criteria provided, single submitter clinical testing Observed in individuals with breast cancer, and a case control study supports this association (Tung et al., 2015; Weitzel et al., 2019; Dorling et al., 2021; Lerner-Ellis et al., 2021; Ding et al., 2023); Published functional studies suggest a damaging effect: decreased DNA damage response in yeast-based assay (Delimitsou et al., 2019); 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: 27621404, 25186627, 31398194, 25318351, 32598223, 33471991, 30851065, 37145128, 32885271, 31206626, 19782031, 22419737, 30262796)
Invitae RCV000199653 SCV000253489 likely pathogenic Familial cancer of breast 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 236 of the CHEK2 protein (p.Leu236Pro). This variant is present in population databases (rs587782471, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with a strong personal and family history of breast cancer and other cancers, with nearly 80% of these families reporting Hispanic ancestry. In the Hispanic population, this variant has been observed more frequently among individuals with breast cancer than among controls (OR=3.2, 95% CI [1.5-6.5], p=0.0016), and has been reported as a possible founder mutation (PMID: 25186627, 25318351, 31206626; Invitae). ClinVar contains an entry for this variant (Variation ID: 142448). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl RCV000199653 SCV000489420 uncertain significance Familial cancer of breast 2016-10-03 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131577 SCV000684681 likely pathogenic Hereditary cancer-predisposing syndrome 2023-10-16 criteria provided, single submitter clinical testing This missense variant replaces leucine with proline at codon 236 in the kinase domain of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Crystal structure studies on CHEK2 place the reference p.Leu236 in the kinase domain near the ATP binding site and implicate it in mediating CHEK2 dimerization, which is required to form an active kinase (PMID: 16794575, 19782031). Functional studies have shown this variant impairs DNA damage response in yeast (PMID: 30851065) and impairs KAP1 phosphorylation and CHK2 autophosphorylation in complementation assays (PMID: 37449874). In the general population, this variant has been reported exclusively in the Latino population and identified in 88/35436 Latino chromosomes by the Genome Aggregation Database (gnomAD). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 30262796, 33471991). A breast cancer case-control study in the Latino population has shown that this variant is associated with increased breast cancer risk with odds ratio of 3.2 (95% CI, 1.5-6.5; P = .002) (PMID: 31206626). This variant has been observed at an increased frequency in individuals affected with breast cancer than in unaffected individuals (Color internal data). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212433 SCV000698815 likely pathogenic Hereditary breast ovarian cancer syndrome 2023-05-05 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.707T>C (p.Leu236Pro) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) 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 0.00035 in 251368 control chromosomes (gnomAD), predominantly at a frequency of 0.0025 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031). However, a relatively recent study performed on a large cohort of Hispanics, reported that the variant is observed more frequently in patients affected with breast cancer than in controls, and the variant was reported as a potential founder mutation in this population (Weitzel_2019). c.707T>C has also been reported in the literature in several individuals (mostly of Hispanic/Latin American origin) affected with HBOC and/or with a positive family/personal history for breast cancer (e.g. Tung_2015, Quezada Urban_2018, SoRelle_2020, Dorling_2021, Chavarri-Guerra_2021, Weitzel_2019, Lerner-Ellis_2021) as well as at least one individual affected with prostate cancer (e.g., Brady_2022). Experimental evidence utilizing an in vivo, yeast-based, functional assay found the variant to restrict growth rate levels to those of the negative control strain carrying the well-known pathogenic CHEK2 variant c.1100delC (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31398194, 27621404, 35467778, 30851065, 33471991, 34404389, 30262796, 32598223, 25186627, 31206626, 25318351, 26580448, 32975687). Multiple ClinVar submitters have assessed the variant since 2014: 8 submitters have classified the variant as likely pathogenic and 3 have classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences RCV000586622 SCV000806886 likely pathogenic not provided 2024-04-08 criteria provided, single submitter clinical testing This variant has been reported to be significantly enriched in females of Hispanic ancestry with breast cancer when compared to controls (OR=2.41, CI=1.87–3.09, p = 5.35×10^12 in Mundt et al. 2023. PubMed ID: 37839337; Weitzel et al. 2019. PubMed ID: 31206626). This variant occurs in the kinase domain of the CHEK2 protein near the ATP binding site (Oliver et al. 2006. PubMed ID: 16794575; Figure 2, Cai et al. 2009. PubMed ID: 19782031; Lountos et al. 2011. PubMed ID: 21963792; Roeb et al. 2012. PubMed ID: 22419737). In addition to breast cancer, this variant has also been reported in an individual with pediatric onset acute lymphoblastic leukemia (Table S4c_TSG, Zhang et al. 2015. PubMed ID: 26580448) and in individuals undergoing hereditary cancer genetic testing (Table 2, Yorczyk et al. 2015. PubMed ID: 25318351; Table 2, Balmaña et al. 2016. PubMed ID: 27621404). Experimental evidence utilizing an in vivo, yeast-based, functional assay found the variant to be damaging (Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.25% of alleles in individuals of Latino descent in gnomAD and has not been observed in other ancestral populations. This variant has conflicting interpretations of uncertain and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142448). Based on this evidence, we interpret this variant as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586622 SCV000888121 likely pathogenic not provided 2022-12-13 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with early onset breast cancer (PMID: 27621404 (2016), 25186627 (2015), 25318351 (2014)). Recent studies indicate this variant is statistically associated with breast cancer in the Hispanic population (PMID: 31206626 (2019)). In a yeast based functional study, this variant has been shown to have deleterious effects on CHEK2 DNA damage response (PMID: 30851065 (2019)). Based on the available information, this variant is classified as likely pathogenic.
Genomic Diagnostics Laboratory, National Institute of Medical Genomics RCV000791342 SCV000928318 likely pathogenic Familial cancer of breast; Li-Fraumeni syndrome 2; Hereditary breast ovarian cancer syndrome 2019-07-17 criteria provided, single submitter clinical testing The Leu236Pro variant in CHEK2 has been reported in individuals with early onset breast cancer (Yorczyk 2014, Tung 2015, Weitzel 2019). Additionally an in vivo functional study in transformed yeast cells indicates that the Leu236Pro variant are incapable of completing DNA replication and entering mitosis (Delimitsou 2019 -PMID:30851065). Also in our laboratory we have found 9 individuals of Mexican ancestry with breast, ovarian, thyroid and central nervous system tumors and high risk criteria. In summary, the variant meets ACMG criteria to be classified as likely pathogenic. (ACMG criteria: PS3, PM1, PP3, BS2)
Division of Medical Genetics, University of Washington RCV000199653 SCV001424792 uncertain significance Familial cancer of breast 2019-08-30 criteria provided, single submitter clinical testing The c.836T>C (p.Leu279Pro) variant has an allele frequency of 0.0003112 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function suggest that this variant may have a deleterious effect. In addition, a functional assay in yeast demonstrated decreased growth compared to wild type in yeast transfected with the p.Leu279Pro variant [PMID: 30851065]. At this time, it is unknown at this time whether or not this variant increases cancer risk; therefore, we interpret it as a variant of uncertain significance.
Baylor Genetics RCV000199653 SCV002096993 likely pathogenic Familial cancer of breast 2021-12-14 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been reported as disease-causing for hereditary beast cancer [PMID:31206626)
Sema4, Sema4 RCV000131577 SCV002537632 likely pathogenic Hereditary cancer-predisposing syndrome 2022-03-04 criteria provided, single submitter curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003153427 SCV003842962 likely pathogenic Predisposition to cancer 2022-12-13 criteria provided, single submitter clinical testing The CHEK2 c.707T>C (p.Leu236Pro) missense change is prevalent in the Latino population with a maximum subpopulation frequency of 0.25% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). A case-control study of BRCA-mutation-negative Hispanic women demonstrated that this variant is associated with increased risk of developing breast cancer in this population, suggesting that this may be a founder variant (PMID: 31206626). The in silico tool REVEL is inconclusive about the effect of this variant on protein function, however an in vivo functional study in yeast suggests a deleterious effect (PMID: 30851065). In summary, this variant meets criteria to be classified as likely pathogenic.
Myriad Genetics, Inc. RCV000199653 SCV004020088 likely pathogenic Familial cancer of breast 2023-03-08 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752].
Illumina Laboratory Services, Illumina RCV003389239 SCV004101362 likely pathogenic Li-Fraumeni syndrome 2 2023-06-12 criteria provided, single submitter clinical testing The CHEK2 c.707T>C (p.Leu236Pro) missense variant has been reported in several individuals with or at elevated risk for primarily breast cancer (PMID: 2531835; 31206626, 32885271, 37145128; DOI:https://doi.org/10.1016/j.clgc.2023.05.012). In a case-control study, p.Leu236Pro was associated with a significantly increased risk of breast cancer risk with an odds ratio of 3.2 (95% CI: 1.5-6.5; p=0.002). It was also reported to have a significant association with estrogen receptor positive tumors (p=0.024) (PMID: 31206626). The highest frequency of this allele in the Genome Aggregation Database is 0.002483 in the Latino/Admixed American population (version 2.1.1), which is higher than expected for a disease-causing variant in this gene. However, it may represent a founder variant in Latin or Indigenous American populations (PMID: 31206626). This variant is in the kinase domain and was shown to impair DNA damage response and growth rate in a yeast-based assay (PMID: 30851065). Based on the collective evidence, the c.707T>C (p.Leu236Pro) variant is classified as likely pathogenic for CHEK2-related cancer susceptibility.
Baylor Genetics RCV000199653 SCV004217477 likely pathogenic Familial cancer of breast 2023-10-26 criteria provided, single submitter clinical testing

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