Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001017150 | SCV001178185 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-03-23 | criteria provided, single submitter | clinical testing | The p.N352Y variant (also known as c.1054A>T), located in coding exon 9 of the CHEK2 gene, results from an A to T substitution at nucleotide position 1054. The asparagine at codon 352 is replaced by tyrosine, an amino acid with dissimilar properties. In one case control study, this alteration was identified in 1/1303 female probands with early-onset breast cancer and in none of 1109 healthy matched controls (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13(1):R). 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 | RCV001860855 | SCV002179403 | uncertain significance | Familial cancer of breast | 2022-05-12 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 21244692). ClinVar contains an entry for this variant (Variation ID: 822086). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 352 of the CHEK2 protein (p.Asn352Tyr). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003479265 | SCV004223385 | uncertain significance | not specified | 2023-11-06 | criteria provided, single submitter | clinical testing | Variant summary: CHEK2 c.1054A>T (p.Asn352Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251292 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1054A>T has been reported in the literature in at least one individual affected with breast cancer without evidence for causality (e.g. LeCalvez-Kelm_2011). 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 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |