Submissions for variant NM_007194.4(CHEK2):c.1526C>T (p.Pro509Leu)

gnomAD frequency: 0.00003  dbSNP: rs587782541

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131748	SCV000186789	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-20	criteria provided, single submitter	clinical testing	The p.P509L variant (also known as c.1526C>T), located in coding exon 13 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1526. The proline at codon 509 is replaced by leucine, an amino acid with similar properties. This variant has been reported in an Ashkenazi Jewish prostate cancer cohort; however, no significant disease association was observed (Tischkowitz M et al. Cancer Lett. 2008 Oct;270:173-80). This variant was also identified in 1/882 Chinese individuals who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657) and in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). 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 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.
GeneDx	RCV000212473	SCV000210996	uncertain significance	not provided	2023-01-11	criteria provided, single submitter	clinical testing	Observed in individuals with breast or prostate cancer (Tischkowitz et al., 2008; Decker et al., 2017); Published functional studies are inconclusive: intermediate impact on cell growth after DNA damage (Delimitsou et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30851065, 31742824, 28779002, 18571837)
Invitae	RCV000469852	SCV000550431	uncertain significance	Familial cancer of breast	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 509 of the CHEK2 protein (p.Pro509Leu). This variant is present in population databases (rs587782541, gnomAD 0.06%). This missense change has been observed in individual(s) with personal or family history of hereditary breast and ovarian cancer and/or prostate cancer (PMID: 18571837, 31742824). ClinVar contains an entry for this variant (Variation ID: 142554). 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 leucine 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). 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	RCV000469852	SCV000785814	uncertain significance	Familial cancer of breast	2017-12-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212473	SCV000888112	uncertain significance	not provided	2023-07-03	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with prostate cancer (PMID: 18571837 (2008)), breast cancer (PMID: 28779002 (2017), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)), and suspected hereditary breast and ovarian cancer syndrome (HBOC) (PMID: 31742824 (2020)). This variant has also been reported in unaffected individuals (PMID: 28779002 (2017), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)). A functional study reported this variant had an intermediate effect on protein function in an in vivo assay (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.00059 (6/10150 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.
Color Diagnostics, LLC DBA Color Health	RCV000131748	SCV000902940	likely benign	Hereditary cancer-predisposing syndrome	2016-03-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155082	SCV003844277	uncertain significance	not specified	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1526C>T (p.Pro509Leu) 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 2.1e-05 in 233646 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1526C>T has been reported in the literature in at least one individuals affected with prostate cancer and in at least one individual undergoing multigene panel testing for a clinical suspicion of hereditary breast and ovarian cancer syndrome (e.g.Tischkowitz_2008, Shao_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A study evaluating the impact of the variant on protein function using an in vivo yeast-based functional assay found the variant to have intermmediate function compared to the WT protein and the negative control (Delimitsou_2019). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131748	SCV004014908	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000469852	SCV004217528	uncertain significance	Familial cancer of breast	2023-09-29	criteria provided, single submitter	clinical testing