Submissions for variant NM_007194.4(CHEK2):c.1618G>T (p.Ala540Ser)

dbSNP: rs767414081

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001012437	SCV001172887	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-17	criteria provided, single submitter	clinical testing	The p.A540S variant (also known as c.1618G>T), located in coding exon 14 of the CHEK2 gene, results from a G to T substitution at nucleotide position 1618. The alanine at codon 540 is replaced by serine, an amino acid with similar properties. This amino acid position is not well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001062056	SCV001226828	uncertain significance	Familial cancer of breast	2022-03-24	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 540 of the CHEK2 protein (p.Ala540Ser). ClinVar contains an entry for this variant (Variation ID: 819676). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated.
GeneDx	RCV001576484	SCV001803686	uncertain significance	not provided	2020-02-10	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as c.1747G>T (p.Ala583Ser)
Baylor Genetics	RCV001062056	SCV004217650	uncertain significance	Familial cancer of breast	2023-06-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004738118	SCV005344534	uncertain significance	CHEK2-related disorder	2024-04-20	no assertion criteria provided	clinical testing	The CHEK2 c.1618G>T variant is predicted to result in the amino acid substitution p.Ala540Ser. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/819676/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.