Submissions for variant NM_007194.4(CHEK2):c.1375G>C (p.Ala459Pro)

gnomAD frequency: 0.00001  dbSNP: rs769729382

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216045	SCV000273198	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-03	criteria provided, single submitter	clinical testing	The p.A459P variant (also known as c.1375G>C), located in coding exon 11 of the CHEK2 gene, results from a G to C substitution at nucleotide position 1375. The alanine at codon 459 is replaced by proline, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. This alteration was reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). In addition, as a missense substitution, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691821	SCV000819614	uncertain significance	Familial cancer of breast	2023-05-20	criteria provided, single submitter	clinical testing	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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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. ClinVar contains an entry for this variant (Variation ID: 229847). This missense change has been observed in individual(s) with breast cancer, neuroblastoma, and/or prostate cancer (PMID: 32906215, 33011440). This variant is present in population databases (rs769729382, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 459 of the CHEK2 protein (p.Ala459Pro). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product.
Color Diagnostics, LLC DBA Color Health	RCV000216045	SCV000913573	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000691821	SCV004217602	uncertain significance	Familial cancer of breast	2024-02-26	criteria provided, single submitter	clinical testing