Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV001182834 | SCV001348429 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-09-29 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with valine at codon 541 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. 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. |
| Invitae | RCV001876072 | SCV002121189 | uncertain significance | Familial cancer of breast | 2023-11-08 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 541 of the CHEK2 protein (p.Ala541Val). This variant is not present in population databases (gnomAD no frequency). 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: 922650). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002240778 | SCV002511772 | uncertain significance | not specified | 2022-04-19 | criteria provided, single submitter | clinical testing | Variant summary: CHEK2 c.1622C>T (p.Ala541Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 233688 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1622C>T has been reported in the literature in settings of multigene panel testing among individuals affected with Hereditary BRCA-negative breast cancer (example, Weitzel_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Ambry Genetics | RCV001182834 | SCV004006455 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-30 | criteria provided, single submitter | clinical testing | The p.A541V variant (also known as c.1622C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1622. The alanine at codon 541 is replaced by valine, an amino acid with similar properties. This alteration was detected in 1/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 0/1189 controls. (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). This alteration was also detected in a Hispanic patient with colon cancer diagnosed at age 49 (Ricker CN et al. Cancer, 2017 Oct;123:3732-3743). 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. |