Submissions for variant NM_007194.4(CHEK2):c.1525C>T (p.Pro509Ser) (rs587780179)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212472	SCV000149913	uncertain significance	not provided	2018-06-05	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.1525C>T at the cDNA level, p.Pro509Ser (P509S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). This variant was observed in at least one individual with prostate cancer, one with breast and uterine cancer, and two others with a history of a Lynch syndrome-associated tumor and/or colon polyps (Tischkowitz 2008, Yurgelun 2015, Castellanos 2017). Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Pro509Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000116004	SCV000186790	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-18	criteria provided, single submitter	clinical testing	The p.P509S variant (also known as c.1525C>T), located in coding exon 13 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1525. The proline at codon 509 is replaced by serine, an amino acid with similar properties. This variant was functional in an in vitro kinase assay and a human cell-based kinase assay measuring KAP1 phosphorylation (Kleiblova P et al. Int. J. Cancer, 2019 10;145:1782-1797). This alteration behaved as semi-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This alteration has been identified in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358) and in an Ashkenazi Jewish patient diagnosed with prostate cancer (Tischkowitz MD et al. Cancer Lett. 2008 Oct;270:173-80). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000200569	SCV000254929	uncertain significance	Familial cancer of breast	2020-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline with serine at codon 509 of the CHEK2 protein (p.Pro509Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. The frequency data for this variant (rs587780179) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been observed in an individual with prostate cancer (PMID: 18571837), an individual with breast, uterine and skin cancers (PMID: 28051113), an individual with breast cancer and an individual with ovarian cancer (PMID: 31050813), an individual with colorectal cancer (PMID: 29596542), and individuals with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 128063). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0). The serine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
Counsyl	RCV000200569	SCV000488484	uncertain significance	Familial cancer of breast	2016-04-14	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000212472	SCV000806873	uncertain significance	not provided	2017-02-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000200569	SCV000839453	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212472	SCV000888111	uncertain significance	not provided	2020-07-08	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000764368	SCV000895403	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate	2018-10-31	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000116004	SCV000902768	likely benign	Hereditary cancer-predisposing syndrome	2016-03-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781300	SCV000919219	uncertain significance	not specified	2019-03-21	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1525C>T (p.Pro509Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 263796 control chromosomes (gnomAD). This frequency is lower than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (9.5e-05 vs 0.00031), allowing no conclusion about variant significance. c.1525C>T has been reported in the literature in individuals affected with various tumor phenotypes (Castellanos 2015, Yurgelun 2015, Tischkowitz 2008). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating decreased function in a yeast based DNA-damage assay that indicated an intermediate functionality for the variant (Delimitsou 2019). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212472	SCV001744642	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000212472	SCV001807138	likely benign	not provided		no assertion criteria provided	clinical testing