Submissions for variant NM_007194.4(CHEK2):c.1028T>C (p.Ile343Thr)

dbSNP: rs863224746

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000195910	SCV000254918	uncertain significance	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 343 of the CHEK2 protein (p.Ile343Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 216640). 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. 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.
Ambry Genetics	RCV000562192	SCV000669225	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-24	criteria provided, single submitter	clinical testing	The p.I343T variant (also known as c.1028T>C), located in coding exon 9 of the CHEK2 gene, results from a T to C substitution at nucleotide position 1028. The isoleucine at codon 343 is replaced by threonine, an amino acid with similar properties. 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.
Counsyl	RCV000195910	SCV000785205	uncertain significance	Familial cancer of breast	2017-06-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001582697	SCV001813944	uncertain significance	not provided	2022-05-31	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22419737, 19782031)
Color Diagnostics, LLC DBA Color Health	RCV000562192	SCV002053363	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 343 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Genetic Services Laboratory, University of Chicago	RCV001818490	SCV002064733	uncertain significance	not specified	2020-08-27	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.1028T>C, in exon 10 that results in an amino acid change, p.Ile343Thr. This sequence change does not appear to have been previously described in patients with CHEK2-related disorders. This sequence change is absent in the gnomAD database. The p.Ile343Thr change affects a highly conserved amino acid residue located in the kinase domain of the CHEK2 protein. The p.Ile343Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile343Thr change remains unknown at this time.
Myriad Genetics, Inc.	RCV000195910	SCV004020142	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.