Submissions for variant NM_007194.4(CHEK2):c.503C>T (p.Thr168Ile)

gnomAD frequency: 0.00001  dbSNP: rs730881684

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160426	SCV000210964	uncertain significance	not provided	2023-06-26	criteria provided, single submitter	clinical testing	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; Observed in individuals with breast (male or female) and/or ovarian cancer, including one patient who also harbored a pathogenic variant in BRCA2 (Kleiblova et al., 2019; Guindalini et al., 2022); Published functional studies suggest a damaging effect: impaired kinase activity (Kleiblova et al., 2019); This variant is associated with the following publications: (PMID: 22419737, 19782031, 31409080, 31050813, 35264596)
Ambry Genetics	RCV000213298	SCV000274302	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-24	criteria provided, single submitter	clinical testing	The p.T168I variant (also known as c.503C>T), located in coding exon 3 of the CHEK2 gene, results from a C to T substitution at nucleotide position 503. The threonine at codon 168 is replaced by isoleucine, an amino acid with similar properties. This variant was functional in an in vitro kinase assay but non-functional in a human cell-based kinase assay also measuring KAP1 phosphorylation (Kleiblová P et al. Klin Onkol, 2019;32:36-50). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000475670	SCV000550509	uncertain significance	Familial cancer of breast	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 168 of the CHEK2 protein (p.Thr168Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and ovarian cancer or male breast cancer (PMID: 31050813, 31409080, 35264596). ClinVar contains an entry for this variant (Variation ID: 182427). 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: 31050813, 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	RCV000475670	SCV000785657	uncertain significance	Familial cancer of breast	2017-10-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000475670	SCV000839488	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213298	SCV000913597	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 168 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies report conflicting results regarding the impact of this variant on CHEK2 phosphorylation activity (PMID: 31050813, 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 31050813, 37449874) and in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000524). This variant has not been identified 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.
Myriad Genetics, Inc.	RCV000475670	SCV004020105	uncertain significance	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000475670	SCV004217508	uncertain significance	Familial cancer of breast	2023-10-15	criteria provided, single submitter	clinical testing
CZECANCA consortium	RCV001270937	SCV001451741	likely pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Department of Genetics, HCU Lozano Blesa	RCV003493466	SCV004242319	likely pathogenic	Li-Fraumeni syndrome 2	2023-05-01	no assertion criteria provided	clinical testing	Variant summary: CHEK2 c.503C>T results in the replacement of Thr168 by an Ile residue (p.Thr168Ile). The variant was identified in 1 out of 396 patients analysed (freq: 0.0025, doi: 10.3389/fgene.2023.1274108). The patient was a man that developed breast cancer at the age of 57 (luminal-Her2+ tumor phenotype). A co-segregation study was done, showing that the mother and one sister developed breast cancer (BC) at the age of 72 and 64 years, respectively, and that an aunt (by the father side) developed BC at the age of 40 years. The variant was checked in the affected proband's sister, but results showed she did not carry the genetic alteration. A second sister that has not developed BC does carry the mutation. These facts prevents clearly establishing the Thr168Ile variant as a predisposition factor for BC from this study. Moreover, Thr168 appears well conserved in vertebrate species, and the replacement of a threonine by an isoleucine represents the introduction of a bulkier residue. Thr168 is located in the FHA domain, its side chain appears buried forming an apparently stabilizing local H-bond network with Asp162, Ser164, and His143, and is far from any other domain or the dimeric surface. Our in-silico study on the protein stability based on relaxation molecular dynamics simulations (doi: 10.3389/fgene.2023.1274108) indicates that Thr168Ile reduces the conformational stability of CHEK2 protein. The variant does not appear reported in gnomAD v4. Other replacements at the same position (T168N, T168P, and T168A) appear classified in ClinVar as of Uncertain Significance. However, functional studies (PMID: 31050813, 31409080) have reported impaired kinase activity for CHEK2. The metapredictor PirePred (relies on verdicts from other 15 predictor or metapredictor tools) classifies Thr168Ile as Pathogenic, whereas the AI-based predictor AlphaMissense and the ACMG classification tool Franklin suggests this variant as Likely Pathogenic. All this information, even if not conclusive, appears to indicate this variant have more chances of being Pathogenic.