Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000491531 | SCV000579745 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-09-07 | criteria provided, single submitter | clinical testing | The c.783+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the MEN1 gene. This alteration has been reported in two unrelated individuals with a clinical diagnosis of MEN1 (Morelli A et al. Eur. J. Endocrinol. 2000 Feb;142:131-7; Wen Z et al. Arq Bras Endocrinol Metabol. 2012 Apr;56:184-9). Furthermore, two different alterations at this same nucleotide position (c.783+1G>T, c.783+1G>C) have also been reported in patients with MEN1 (Giraud S et al. Am. J. Hum. Genet. 1998 Aug;63:455-67; Poncin J et al. Hum. Mutat. 1999;13:54-60). 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as a disease-causing mutation. |
| ARUP Laboratories, |
RCV000506752 | SCV000604214 | pathogenic | not specified | 2017-02-05 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000697334 | SCV000825936 | pathogenic | Multiple endocrine neoplasia, type 1 | 2022-05-08 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 4 of the MEN1 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 MEN1 are known to be pathogenic (PMID: 12112656, 17853334). This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 10664520, 22666734). This variant is also known as c.893+1G>A or IVS4+1T>A. ClinVar contains an entry for this variant (Variation ID: 428081). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.783+1G>C and c.783+1G>T nucleotide in the MEN1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9683585, 9888389). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000697334 | SCV002547633 | pathogenic | Multiple endocrine neoplasia, type 1 | 2022-05-02 | criteria provided, single submitter | clinical testing | Variant summary: MEN1 c.783+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in exon skipping (Hai_2000). The variant allele was found at a frequency of 4e-06 in 251124 control chromosomes. c.783+1G>A has been reported in the literature (as 893+1G>A or IVS4+1G>A) in individuals affected with Multiple Endocrine Neoplasia Type 1 (example, Hai_2000, Marini_2018, Nunes_2014). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Genome Sciences Centre, |
RCV000515529 | SCV000611149 | likely pathogenic | Metastatic pancreatic neuroendocrine tumours | 2017-11-01 | no assertion criteria provided | research |