ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.665T>C (p.Met222Thr)

gnomAD frequency: 0.00001  dbSNP: rs775134484
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204561 SCV000259903 uncertain significance Familial cancer of breast 2023-12-13 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 222 of the CHEK2 protein (p.Met222Thr). This variant is present in population databases (rs775134484, gnomAD 0.02%). 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: 219820). 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 tolerated. 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.
Counsyl RCV000204561 SCV000489730 uncertain significance Familial cancer of breast 2016-11-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000570800 SCV000666373 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-04 criteria provided, single submitter clinical testing The p.M222T variant (also known as c.665T>C), located in coding exon 4 of the CHEK2 gene, results from a T to C substitution at nucleotide position 665. The methionine at codon 222 is replaced by threonine, an amino acid with similar properties. This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health RCV000570800 SCV001355162 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-19 criteria provided, single submitter clinical testing This missense variant replaces methionine with threonine at codon 222 of the CHEK2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. 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 been identified in 5/259388 chromosomes 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.
Myriad Genetics, Inc. RCV000204561 SCV004020154 uncertain significance Familial cancer of breast 2023-03-08 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

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