ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1234A>C (p.Ser412Arg)

dbSNP: rs2052550972
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001227058 SCV001399396 uncertain significance Familial cancer of breast 2023-09-29 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 412 of the CHEK2 protein (p.Ser412Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34903604). ClinVar contains an entry for this variant (Variation ID: 954575). 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. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 34903604). 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.
Sema4, Sema4 RCV002258168 SCV002537035 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-19 criteria provided, single submitter curation
Ambry Genetics RCV002258168 SCV002663920 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-14 criteria provided, single submitter clinical testing The p.S412R variant (also known as c.1234A>C), located in coding exon 10 of the CHEK2 gene, results from an A to C substitution at nucleotide position 1234. The serine at codon 412 is replaced by arginine, an amino acid with dissimilar properties. 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.
Color Diagnostics, LLC DBA Color Health RCV002258168 SCV004361354 uncertain significance Hereditary cancer-predisposing syndrome 2022-04-18 criteria provided, single submitter clinical testing This missense variant replaces serine with arginine at codon 412 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study using a mouse embryonic stem cell-based assay has shown this variant impairs CHEK2's ability to phosphorylate KAP1 at p.S473 ( PMID: 34903604). 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.

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