Submissions for variant NM_007194.4(CHEK2):c.1000G>C (p.Ala334Pro)

dbSNP: rs864622371

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521044	SCV000618470	uncertain significance	not provided	2017-05-08	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.1000G>C at the cDNA level, p.Ala334Pro (A334P) at the protein level, and results in the change of an Alanine to a Proline (GCT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Ala334Pro was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Alanine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. CHEK2 Ala334Pro occurs at a position that is conserved across species and is located in the protein kinase domain (Desrichard 2011, Roeb 2012, UniProt). 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 Ala334Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000777176	SCV000912867	uncertain significance	Hereditary cancer-predisposing syndrome	2018-11-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000777176	SCV002661331	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-05	criteria provided, single submitter	clinical testing	The p.A334P variant (also known as c.1000G>C), located in coding exon 8 of the CHEK2 gene, results from a G to C substitution at nucleotide position 1000. The alanine at codon 334 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. 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.
Invitae	RCV002525145	SCV003230906	uncertain significance	Familial cancer of breast	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 334 of the CHEK2 protein (p.Ala334Pro). 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: 449971). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492088	SCV004240439	uncertain significance	Breast and/or ovarian cancer	2023-05-01	criteria provided, single submitter	clinical testing