Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002381254 | SCV002690031 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-03-29 | criteria provided, single submitter | clinical testing | The c.1350+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the MEN1 gene. This alteration has been reported in a Chilean family with familial isolated hyperparathyroidism. RNA analyses on patient leukocytes demonstrated that c.1350+1G>A results in intron retention (Carrasco et al. J Clin Endoc Metab 2004 Aug; 89(8): 4124-9). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, 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 a disease-causing mutation. |
| Invitae | RCV003517126 | SCV004295812 | pathogenic | Multiple endocrine neoplasia, type 1 | 2023-08-14 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Ser555Asn) have been determined to be pathogenic (PMID: 9683585, 15254225, 21819486). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in retention of intron 9 which introduces a premature stop codon and introduces a new termination codon (PMID: 29416715). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 16707). Disruption of this splice site has been observed in individual(s) with hyperparathyroidism and/or multiple endocrine neoplasia type 1 (PMID: 15292357, 29416715). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 of the MEN1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. |
| OMIM | RCV000018187 | SCV000038466 | pathogenic | Hyperparathyroidism 1 | 2004-08-01 | no assertion criteria provided | literature only |