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

gnomAD frequency: 0.00014  dbSNP: rs587780179

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212472	SCV000149913	uncertain significance	not provided	2021-07-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: intermediate to normal activity with respect to DNA damage response and kinase activity (Delimitsou 2019, Kleiblova 2019); Observed in individuals with breast, ovarian, prostate, and other cancers (Tischkowitz 2008, Yurgelun 2015, Castellanos 2017, Kleiblova 2019); This variant is associated with the following publications: (PMID: 32906215, 27535533, 31050813, 31422574, 30851065, 29596542, 28420421, 28051113, 18571837, 25980754)
Ambry Genetics	RCV000116004	SCV000186790	likely benign	Hereditary cancer-predisposing syndrome	2024-03-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200569	SCV000254929	uncertain significance	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 509 of the CHEK2 protein (p.Pro509Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer, colorectal cancer, Lynch syndrome, ovarian cancer, prostate cancer, skin cancer, and/or uterine cancer (PMID: 18571837, 25980754, 28051113, 29596542, 31050813). 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065, 31409080). 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, part of Exact Sciences	RCV004528805	SCV000806873	uncertain significance	CHEK2-related disorder	2022-08-23	criteria provided, single submitter	clinical testing	The CHEK2 c.1525C>T variant is predicted to result in the amino acid substitution p.Pro509Ser. This variant was reported in a patient with prostate cancer of Ashkenazi Jewish origin (Tischkowitz et al. 2008, PubMed ID: 18571837) and also in two individuals with suspected Lynch syndrome (Yurgelun et al. 2015, Supplemental Table 2, PubMed ID: 25980754). This variant is reported in 0.020% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29085140-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128063/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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	2024-07-12	criteria provided, single submitter	clinical testing	The CHEK2 c.1525C>T (p.Pro509Ser) variant has been reported in the published literature in individuals with prostate cancer (PMID: 18571837 (2008)), breast cancer (PMID: 28051113 (2017), PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)), uterine cancer (PMID: 28051113 (2017)), colorectal cancer (PMID: 29596542 (2018)), suspected Lynch syndrome (PMID: 25980754 (2015)), and suspected hereditary cancer (PMID: 32906215 (2020)). This variant has also been reported in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)). Functional studies reported conflicting results of this variant's effect on CHEK2 function (PMID: 30851065 (2019), 31050813 (2019), 34903604 (2021), 37449874 (2023)). The frequency of this variant in the general population, 0.0002 (3/15176 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000764368	SCV000895403	uncertain significance	Familial cancer of breast; CHEK2-related cancer predisposition; Bone osteosarcoma; Prostate cancer	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	2024-08-01	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 8.1e-05 in 233628 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.1e-05 vs 0.00031), allowing no conclusion about variant significance. c.1525C>T has been reported in the literature in individuals affected with breast cancer, prostate cancer, Lynch syndrome, and other cancers (e.g. Castellanos_2015, Lu_2016, Yurgelun_2015, Tischowitz_2008, Nunziato_2022, Vargas-Parra_2020, Boonen_2022), although it has also been reported in healthy individuals (e.g. Kraemer_2019, Boonen_2022, FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome or other CHEK2-related cancers. Several publications report experimental evidence evaluating an impact on protein function. A yeast-based DNA-damage assay indicated an intermediate functionality for the variant (Delimitsou_2019), whereas studies in Chek2 knockout mouse embryonic stem cells and in human RPE1-CHEK2-knockout cells found no damaging effect of the variant on its ability to phosphorylate its downstream target KAP1 (Boonen_2022, Stolarova_2023). The following publications have been ascertained in the context of this evaluation (PMID: 28051113, 30851065, 31422574, 27023146, 26644315, 18571837, 25980754, 37449874, 36035419, 32906215, 34903604). ClinVar contains an entry for this variant (Variation ID: 128063). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sema4, Sema4	RCV000116004	SCV002537390	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-16	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000212472	SCV004011385	uncertain significance	not provided	2023-04-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000200569	SCV004020209	likely benign	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Fulgent Genetics, Fulgent Genetics	RCV005025184	SCV005661007	uncertain significance	CHEK2-related cancer predisposition; Bone osteosarcoma; Familial prostate cancer	2024-02-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000781300	SCV005872379	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005359096	SCV005912001	uncertain significance	Li-Fraumeni syndrome; Hereditary breast ovarian cancer syndrome; Familial colorectal cancer type X	2024-01-15	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483482	SCV004228516	not provided	Familial cancer of breast; Prostate cancer; Colorectal cancer		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 11-29-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.