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

gnomAD frequency: 0.00201  dbSNP: rs17883862

Total submissions: 25

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	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000196893	SCV000252812	benign	Familial cancer of breast	2024-02-01	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
CeGaT Center for Human Genetics Tuebingen	RCV000513573	SCV000609075	likely benign	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	RCV000120551	SCV000889330	benign	not specified	2021-08-06	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	RCV000513573	SCV001471358	benign	not provided	2020-12-17	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001797994	SCV002043399	likely benign	Breast and/or ovarian cancer	2022-05-02	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225260	SCV002505169	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132520	SCV002537413	benign	Hereditary cancer-predisposing syndrome	2020-08-24	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000196893	SCV004020192	likely benign	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120551	SCV004024669	uncertain significance	not specified	2023-08-15	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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000513573	SCV001956886	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513573	SCV001968043	likely benign	not provided		no assertion criteria provided	clinical testing