ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.254C>T (p.Pro85Leu) (rs17883862)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 20
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120551 SCV000167696 benign not specified 2013-11-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000132520 SCV000187617 benign Hereditary cancer-predisposing syndrome 2016-06-20 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV000196893 SCV000252812 benign Familial cancer of breast 2020-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000196893 SCV000488524 likely benign Familial cancer of breast 2016-04-25 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000132520 SCV000576431 likely benign Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120551 SCV000594109 likely benign not specified 2017-01-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120551 SCV000601163 benign not specified 2016-09-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513573 SCV000609075 likely benign not provided 2017-05-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132520 SCV000684619 benign Hereditary cancer-predisposing syndrome 2014-12-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000513573 SCV000698792 likely benign not provided 2017-08-09 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.254C>T (p.Pro85Leu) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 143/130972 control chromosomes (1 homozygote) including ExAC, predominantly observed in the African subpopulation at a frequency of 0.007411 (77/10390). This frequency is about 24 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant has been reported in multiple breast cancer patients without clear evidence supporting causality. Although one functional study showed in vitro kinase actitiy of CHEK2 p.P85L was 40-50% of wild-type CHEK2, two additional functional studies showed this variant does not affect yeast growth rate or in vivo response to DNA damage. In addition, multiple clinical laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000513573 SCV000889330 benign not provided 2016-09-21 criteria provided, single submitter clinical testing
Mendelics RCV000196893 SCV001141376 likely benign Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285043 SCV001471358 benign none provided 2020-02-14 criteria provided, single submitter clinical testing
OMIM RCV000005942 SCV000026124 pathogenic Bone osteosarcoma 2002-01-01 no assertion criteria provided literature only
ITMI RCV000120551 SCV000084705 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355309 SCV001550162 benign Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Pro85Leu variant was identified in 31 of 5508 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer and was present in 31 of 6844 control chromosomes (frequency: 0.005) from healthy individuals (Bell 2007, Shaag 2005, Le Calvez-Kelm 2011, Bodian 2014). The variant was also identified in dbSNP (ID: rs17883862 as With Pathogenic, Uncertain significance allele), ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Quest Diagnostics Nichols Institute San Juan Capistrano, and Color Genomics and as likely benign by Counsyl and four other clinical laboratories) and the Zhejiang University Database (as neutral allele). The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 285 of 277140 chromosomes (1 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). This variant was observed in the following populations: African in 192 of 24018 chromosomes (freq: 0.008), Ashkenazi Jewish in 39 of 10152 chromosomes (freq: 0.004), Latino in 33 of 34416 chromosomes (freq: 0.001), Other in 1 of 6460 chromosomes (freq: 0.0002), European in 18 of 126662 chromosomes (freq: 0.0001), and South Asian in 2 of 30780 chromosomes (freq: 0.0001), but not in the East Asian or Finnish populations. The p.Pro85 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing. Several in vitro studies show DNA damage response by this variant is consistent with that of the wild-type protein (Nevanlinna 2006, Shaag 2005, Roeb 2012). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000120551 SCV001809445 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000513573 SCV001905946 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000120551 SCV001929080 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000513573 SCV001956886 likely benign not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.