Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000166874 | SCV000217690 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-11-30 | criteria provided, single submitter | clinical testing | The c.1867+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 15 in the MRE11A gene. This alteration was detected in 1/715 male breast cancer patients who underwent multi-gene panel testing at a clinical diagnostic laboratory (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 02;161:575-586). This alteration was also identified in a cohort of 192 Spanish hereditary breast and ovarian cancer families who did not have a pathogenic variant in BRCA1 or BRCA2 (Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513) as well as in a cohort of 7768 adult ovarian cancer cases of European ancestry referred to a single clinical testing laboratory (Lilyquist J et al. Gynecol Oncol, 2017 Nov;147:375-380). This variant was also identified by whole genome sequencing in an individual with an immunodeficiency disorder; it was seen in conjunction with another MRE11A deep intronic alteration (van Schouwenburg PA et al. Clin. Immunol., 2015 Oct;160:301-14). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV001378979 | SCV001576690 | likely pathogenic | Ataxia-telangiectasia-like disorder | 2024-11-27 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 16 of the MRE11 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MRE11 are known to be pathogenic (PMID: 23080121, 23912341). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with combined variable immunodeficiency, breast and ovarian cancer (PMID: 26122175, 28008555, 28888541, 34009545). ClinVar contains an entry for this variant (Variation ID: 187174). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Revvity Omics, |
RCV001781515 | SCV002017545 | pathogenic | Ataxia-telangiectasia-like disorder 1 | 2019-03-15 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV001781515 | SCV004193769 | likely pathogenic | Ataxia-telangiectasia-like disorder 1 | 2024-01-10 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV001781515 | SCV005631424 | likely pathogenic | Ataxia-telangiectasia-like disorder 1 | 2024-05-31 | criteria provided, single submitter | clinical testing |