Submissions for variant NM_007194.4(CHEK2):c.1247T>C (p.Ile416Thr)

dbSNP: rs1555913642

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523357	SCV000618408	uncertain significance	not provided	2017-04-13	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.1247T>C at the cDNA level, p.Ile416Thr (I416T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Ile416Thr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Ile416Thr occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located within the protein kinase domain (Desrichard 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CHEK2 Ile416Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804063	SCV000943956	uncertain significance	Familial cancer of breast	2023-07-10	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 416 of the CHEK2 protein (p.Ile416Thr). 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: 449933). 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	RCV001010552	SCV001170773	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-11	criteria provided, single submitter	clinical testing	The p.I416T variant (also known as c.1247T>C), located in coding exon 10 of the CHEK2 gene, results from a T to C substitution at nucleotide position 1247. The isoleucine at codon 416 is replaced by threonine, an amino acid with similar properties. This amino acid position is well 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.
Color Diagnostics, LLC DBA Color Health	RCV001010552	SCV001342742	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000804063	SCV004217534	uncertain significance	Familial cancer of breast	2023-09-28	criteria provided, single submitter	clinical testing