Submissions for variant NM_007194.4(CHEK2):c.1160C>T (p.Thr387Ile)

dbSNP: rs587780168

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115985	SCV000149894	uncertain significance	not provided	2017-05-05	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.1160C>T at the cDNA level, p.Thr387Ile (T387I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). While residue Thr387 has been show in both in vitro and in vivo assays to be involved in oligomerization and phosphorylation, CHEK2 Thr387Ile has not been functionally evaluated (Schwarz 2003). CHEK2 Thr387Ile was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Thr387Ile occurs at a position that is conserved across species and is located in the kinase domain (Desrichard 2011, Roeb 2012). 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 Thr387Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000531635	SCV000633104	uncertain significance	Familial cancer of breast	2024-01-07	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 387 of the CHEK2 protein (p.Thr387Ile). This variant is present in population databases (rs587780168, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 30613976, 35886069). This variant is also known as c.1289C>T (p.Thr430Ile). ClinVar contains an entry for this variant (Variation ID: 128047). 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	RCV000571263	SCV000661748	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	clinical testing	The p.T387I variant (also known as c.1160C>T), located in coding exon 10 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1160. The threonine at codon 387 is replaced by isoleucine, an amino acid with similar properties. The Thr-387 residue is an autophosphorylation site located within the activation loop of the Chk2 kinase domain, and has been demonstrated to have a dependency on Chk2 kinase activity for phosphorylation (Wu X et al. Hum. Mutat. 2006 Aug;27(8):742-7; Schwarz JK et al. Mol. Cancer Res. 2003 Jun; 1(8):598-609). This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Color Diagnostics, LLC DBA Color Health	RCV000571263	SCV000689635	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-26	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 387 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, however the Thr387 residue has been shown to be important for CHEK2 kinase activity (PMID: 11390408, 12805407, 16835864, 20713355). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251014 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307396	SCV002600707	uncertain significance	not specified	2022-10-24	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1160C>T (p.Thr387Ile) 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 4e-06 in 251014 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1160C>T has been reported in the literature in at least one male individual affected with Breast Cancer. This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.