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

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000116004	SCV000186790	uncertain significance	Hereditary cancer-predisposing syndrome	2017-09-13	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color	RCV000116004	SCV000902768	likely benign	Hereditary cancer-predisposing syndrome	2016-03-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000200569	SCV000488484	uncertain significance	Familial cancer of breast	2016-04-14	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
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.
Integrated Genetics/Laboratory Corporation of America	RCV000781300	SCV000919219	uncertain significance	not specified	2017-12-26	criteria provided, single submitter	clinical testing	Variant summary: The CHEK2 c.1525C>T (p.Pro509Ser) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 3/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 19/229292 control chromosomes (gnomAD and publication controls) at a frequency of 0.0000829, which is approximately 3 times the estimated maximal expected allele frequency of a LFS-causing CHEK2 variant (0.0000284), suggesting this variant is possibly a rare benign polymorphism. This variant has been reported as a germline variant in two cancer patients. One with breast cancer, skin cancer, uterine cancer and thyroidectomy due to multinodular hyperplasia in whom a potentially deleterious variant in another gene (FANCL, c.1111_1114dupATTA; p.Thr372Asnfs*, not classified at our laboratory) was identified (Castellanos_2015). It was also reported in another patient with Lynch syndromeassociated cancer and/or polyps (Yurgelun_2015). Lastly, it has been reported somatically in a CRC patient (Russo_2016) and in one patient with CRC (Lu_2016) in whom origin of the variant is unknown. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. To our knowledge, no functional studies describing an impact on protein function have been reported. Taken together, this variant is classified as Variant of Unknown Significance.
Invitae	RCV000200569	SCV000254929	uncertain significance	Familial cancer of breast	2018-12-18	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), 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.
Mendelics	RCV000200569	SCV000839453	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
PreventionGenetics	RCV000212472	SCV000806873	uncertain significance	not provided	2017-02-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212472	SCV000888111	uncertain significance	not provided	2018-05-25	criteria provided, single submitter	clinical testing