Submissions for variant NM_007194.4(CHEK2):c.1243G>A (p.Val415Ile)

dbSNP: rs1601721900

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001010510	SCV001170722	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-05	criteria provided, single submitter	clinical testing	The p.V415I variant (also known as c.1243G>A), located in coding exon 10 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1243. The valine at codon 415 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	RCV001010510	SCV001343119	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 415 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
Invitae	RCV001216088	SCV001387865	uncertain significance	Familial cancer of breast	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 415 of the CHEK2 protein (p.Val415Ile). 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: 818682). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230617	SCV003928334	uncertain significance	not specified	2023-04-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003230617	SCV004243016	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing