Submissions for variant NM_007194.4(CHEK2):c.1451C>T (p.Pro484Leu)

gnomAD frequency: 0.00036  dbSNP: rs564605612

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129213	SCV000183963	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	The p.P484L variant (also known as c.1451C>T), located in coding exon 12 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1451. The proline at codon 484 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in 1/1303 breast cancer patients and was absent from 1109 healthy controls (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration was detected in 1/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 0/1189 controls (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). This variant was reported in 5/60,466 breast cancer cases and in 1/53,461 controls in another study (Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition, this alteration has been detected in a cohort of 122 patients who underwent multi-gene panel testing for hereditary cancer after having previously tested negative for mutations in BRCA1 and BRCA2 (Yadav S et al. Fam. Cancer. 2017 07;16:319-328). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 05;40(5):631-648). However, another in vitro kinase assay showed p.P484L to be damaging (Dutil J et al. Sci. Rep. 2019 11;9(1):17769). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000590757	SCV000210993	uncertain significance	not provided	2024-07-17	criteria provided, single submitter	clinical testing	Published functional studies are conflicting: some studies demonstrate autophosphorylation and kinase activity comparable to wild type, while others demonstrate reduced stability and decreased kinase activity (PMID: 30851065, 31780696, 37449874); Observed in individuals with a personal or family history of breast cancer as well as in unaffected controls (PMID: 21244692, 25186627, 28102005, 27878467, 31780696, 33471991); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25186627, 21244692, 26787654, 27878467, 28102005, 31106920, 30851065, 31780696, 32310333, 31742824, 34008015, 35493704, 32885271, 33471991, 22419737, 19782031, 37449874)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206213	SCV000261439	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 leucine, which is neutral and non-polar, at codon 484 of the CHEK2 protein (p.Pro484Leu). This variant is present in population databases (rs564605612, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer and/or mesothelioma (PMID: 21244692, 25186627, 31206626, 31780696, 34008015). ClinVar contains an entry for this variant (Variation ID: 140938). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065, 31780696). 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	RCV000206213	SCV000488328	uncertain significance	Familial cancer of breast	2016-02-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129213	SCV000537531	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 484 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has demonstrated this variant to be benign in a yeast-based DNA damage repair assay (PMID: 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 21244692, 25186627, 31780696, Lovejoy 2018, 33471991), prostate cancer (PMID: 31214711), or had a personal or family history of breast and/or ovarian cancer (PMID: 31742824). This variant has also been identified in 22/265184 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590757	SCV000601156	uncertain significance	not provided	2023-08-10	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 33471991 (2021) see also LOVD https://databases.lovd.nl/shared/variants/CHEK2), 31742824 (2020), 31206626 (2019), 31780696 (2019), 25186627 (2015), and 21244692 (2011)). This variant has been reported to have no effect on CHEK2 DNA damage response (PMID: 30851065 (2019)), however additional studies are required to determine the global effect of this variant on CHEK2 protein function. The frequency of this variant in the general population, 0.000081 (10/124182 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV002478384	SCV000611453	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer	2021-08-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212468	SCV000698780	uncertain significance	not specified	2024-04-10	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1451C>T (p.Pro484Leu) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 236006 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.6e-05 vs 0.00031), allowing no conclusion about variant significance. c.1451C>T has been reported in the literature in individuals affected with breast and other cancers (e.g. Young_2016, Calvez-Kelm_2011, Tung_2014, Yadav_2016, Dutil_2019, Shao_2019, Weitzel_2019, Dorling_2021, Cheung_2021), but have also been seen in individuals over age 70 with no history of cancer (FLOSSIES database). These data do not allow any conclusion about variant significance. Several publications report experimental evidence evaluating an impact on protein function, with conflicting results. The variant was classified as benign following assessment in a yeast-based assay (Delimitsou_2019), but was shown to significantly reduce kinase activity when expressed in HEK293T cells (Duhl_2019). The following publications have been ascertained in the context of this evaluation (PMID: 21244692, 25186627, 26787654, 27878467, 30851065, 31206626, 31742824, 31780696, 33471991, 34008015). ClinVar contains an entry for this variant (Variation ID: 140938). Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798435	SCV002043394	uncertain significance	Breast and/or ovarian cancer	2021-01-08	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212468	SCV002066654	uncertain significance	not specified	2020-10-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.1451C>T, in exon 13 that results in an amino acid change, p.Pro484Leu. This sequence change has been described in the gnomAD database with a frequency of 0.03% in the Latino sub-population (dbSNP rs564605612). The p.Pro484Leu change has been reported in individuals with breast cancer (PMIDs: 21244692, 25186627, 31780696). Functional studies have demonstrated conflicting results; Dutil et al., 2019 reported dramatically decreased levels of protein expression compared to wild type, while Delimitsou et al., 2019 reported that this variant did not have a substantial impact on protein function (PMIDs: 31780696, 30851065). The p.Pro484Leu change affects a highly conserved amino acid residue located in a domain of the CHEK2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro484Leu substitution. Due to these contrasting evidences, the clinical significance of the p.Pro484Leu change remains unknown at this time.
Sema4, Sema4	RCV000129213	SCV002537378	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000206213	SCV004020186	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].
Baylor Genetics	RCV000206213	SCV004217497	uncertain significance	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000590757	SCV004225579	uncertain significance	not provided	2022-03-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528849	SCV004110222	uncertain significance	CHEK2-related disorder	2024-01-02	no assertion criteria provided	clinical testing	The CHEK2 c.1451C>T variant is predicted to result in the amino acid substitution p.Pro484Leu. This variant has been observed in individuals with breast cancer, but its pathogenicity was not established (Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Tung et al. 2014. PubMed ID: 25186627; Yadav et al. 2017. PubMed ID: 27878467; Shao et al. 2020. PubMed ID: 31742824). An in vitro functional assay showed that this variant leads to decreased kinase activity (Dutil et al. 2019. PubMed ID: 31780696). This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140938/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.