Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000212409 | SCV000211008 | uncertain significance | not provided | 2021-04-15 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate impaired cell growth following DNA damage in a yeast-based in vivo assay (Delimitsou 2019); This variant is associated with the following publications: (PMID: 30851065, 33298767) |
Ambry Genetics | RCV000160447 | SCV000217869 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-12-22 | criteria provided, single submitter | clinical testing | The p.W93R variant (also known as c.277T>C), located in coding exon 1 of the CHEK2 gene, results from a T to C substitution at nucleotide position 277. The tryptophan at codon 93 is replaced by arginine, an amino acid with dissimilar properties. This variant was detected in a patient with breast cancer diagnosed at age 61 and 71 (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This variant behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). 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 | RCV000205700 | SCV000259375 | uncertain significance | Familial cancer of breast | 2023-12-22 | criteria provided, single submitter | clinical testing | This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 93 of the CHEK2 protein (p.Trp93Arg). This variant is present in population databases (rs730881697, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 182447). 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. 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. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000212409 | SCV000889331 | uncertain significance | not provided | 2017-12-29 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000160447 | SCV000913603 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-03 | criteria provided, single submitter | clinical testing | This missense variant replaces tryptophan with arginine at codon 93 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). This variant has been shown to impact function in a yeast DNA repair assay (PMID: 30851065) and in a kinase assay (PMID: 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 32885271, 37449874), and in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000228). This variant has been identified in 1/251224 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. |
Department of Pathology and Laboratory Medicine, |
RCV001354516 | SCV001549153 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The CHEK2 p.Trp93Arg variant was not identified in the literature. The variant was identified in dbSNP (rs730881697) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Color, Ambry Genetics and 2 other submitters). The variant was identified in control databases in 1 of 246,184 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111,672 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. A yeast-based functional assay showed that the variant had a damaging effect on cell function (Delimitsou 2019). The p.Trp93 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |