Submissions for variant NM_007194.4(CHEK2):c.1501G>A (p.Glu501Lys)

gnomAD frequency: 0.00001  dbSNP: rs17883172

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160440	SCV000210994	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	Published functional studies suggest no damaging effect: normal cell growth after MMS-induced DNA damage (PMID: 30851065); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.1630G>A, p.Glu544Lys; This variant is associated with the following publications: (PMID: 23806170, 27527004, 27498913, 31398194, 22419737, 19782031, 30851065)
Invitae	RCV000205886	SCV000259637	likely benign	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000213437	SCV000276094	likely benign	Hereditary cancer-predisposing syndrome	2021-09-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Counsyl	RCV000205886	SCV000488577	uncertain significance	Familial cancer of breast	2016-05-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160440	SCV000888109	uncertain significance	not provided	2019-10-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213437	SCV000910698	likely benign	Hereditary cancer-predisposing syndrome	2015-04-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000213437	SCV002537385	likely benign	Hereditary cancer-predisposing syndrome	2020-10-12	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265635	SCV002548442	likely benign	not specified	2022-05-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000205886	SCV004020120	uncertain significance	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356202	SCV001551306	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Glu501Lys variant was identified in 4 of 290 proband chromosomes (frequency: 0.014) from individuals or families with breast and / or ovarian cancer (Rashid 2013). The variant was also identified in the following databases: dbSNP (ID: rs17883172) as “With other allele”, ClinVar (4x, as likely benign by Invitae and as uncertain significance by GeneDx, Ambry Genetics and Counsyl), Clinvitae (3x by Invitae and ClinVar), Zhejiang Colon Cancer Database (1x, "reported as pathogenic"). The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 114 of 229076 chromosomes at a frequency of 0.0005 in the following populations: African in 2 of 13836 chromosomes (freq. 0.00014), other in 2 of 5292 chromosomes (freq. 0.0004), South Asian in 110 of 30506 chromosomes (freq. 0.004), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Glu501 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.