ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.322T>A (p.Cys108Ser)

gnomAD frequency: 0.00001  dbSNP: rs730881681
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165829 SCV000216576 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-28 criteria provided, single submitter clinical testing The p.C108S variant (also known as c.322T>A), located in coding exon 2 of the CHEK2 gene, results from a T to A substitution at nucleotide position 322. The cysteine at codon 108 is replaced by serine, an amino acid with dissimilar properties. This alteration was not seen in 732 breast cancer patients or 189 colorectal cancer patients but was detected in 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). 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.
Invitae RCV001049058 SCV001213092 uncertain significance Familial cancer of breast 2022-11-10 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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 186263). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is present in population databases (rs730881681, gnomAD 0.01%). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 108 of the CHEK2 protein (p.Cys108Ser).

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