Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000115914 | SCV000184917 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-10-17 | criteria provided, single submitter | clinical testing | The c.21-6_26del12 variant, which spans part of coding exon 2 of the MRE11A gene, results from a deletion of 12 nucleotides between positions 21-6 and 26, and removes the canonical splice acceptor sequence at c.21-2_-1. This alteration has been previously reported as a splicing mutation detected in a breast/ovarian cancer family (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011;108:18032-7). In addition, c.21-6_26del12 was reported in an individual with colorectal cancer diagnosed under age 55 with at least one first degree relative with colorectal cancer (Chubb D et al. Nat Commun 2016 Jun;7:11883). Based on two different splice site prediction tools, this alteration is expected to abolish the native splice acceptor site; however, experimental evidence is not available. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. |
| University of Washington Department of Laboratory Medicine, |
RCV000115914 | SCV000266187 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-11-20 | criteria provided, single submitter | clinical testing | |
| Illumina Laboratory Services, |
RCV000778135 | SCV000914264 | uncertain significance | Ataxia-telangiectasia-like disorder 1 | 2019-04-05 | criteria provided, single submitter | clinical testing | The MRE11A c.21-6_26delATATAGTGATGA variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.21-6_26delATATAGTGATGA variant has not been reported in the literature in association with ataxia-telangiectasia-like disorder. It has, however, been reported in at least two studies in which it is found in a heterozygous state in two individuals, including in one individual with stage 3c/grade 3 serous ovarian cancer and a personal and family history of breast cancer who carried a truncating variant in BRCA2, and in one individual with early-onset colorectal cancer who did not meet Amsterdam II criteria despite a first-degree relative with colorectal cancer (Walsh et al. 2011; Chubb et al. 2016). The c.21-6_26delATATAGTGATGA variant was absent from 5,226 controls but is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Genome Aggregation Database. Using RT-PCR, analysis of mRNA from the individual with ovarian cancer suggests that this variant alters splicing and results in a frameshift and early termination of the coding sequence (Walsh et al. 2011). Due to the potential impact of splice acceptor variants and limited evidence, the c.21-6_26delATATAGTGATGA variant is classified as a variant of unknown significance but suspicious for pathogenicity for ataxia-telangiectasia-like disorder. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Invitae | RCV001043632 | SCV001207388 | likely pathogenic | Ataxia-telangiectasia-like disorder | 2023-05-11 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 127979). This variant has been observed in individual(s) with ovarian and colorectal cancer (PMID: 22006311, 27329137). This variant is present in population databases (rs587780138, gnomAD 0.003%). This variant results in the deletion of part of exon 3 (c.21-6_26del) 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). |
| Baylor Genetics | RCV000778135 | SCV004193821 | likely pathogenic | Ataxia-telangiectasia-like disorder 1 | 2023-08-07 | criteria provided, single submitter | clinical testing |