ClinVar Genomic variation as it relates to human health

Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Identified in patients with a personal and/or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (Cardinal 2005, Chiloiro 2019); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31249555, 9893679, 15635078)

Variant summary: MEN1 c.1548dupG (p.Lys517GlufsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.2e-06 in 239266 control chromosomes. c.1548dupG has been reported in the literature in individuals affected with Multiple Endocrine Neoplasia Type 1 (Barsch_1998, Cardinal_2006, Chiloiro_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Lys517Glufs*14) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 94 amino acid(s) of the MEN1 protein. This variant is present in population databases (rs761695866, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with a personal and family history of pancreatic neuroendocrine tumors, pituitary adenomas and hyperparathyroidism (PMID: 15635078, 31249555). This variant is also known as 1548–1549insG. ClinVar contains an entry for this variant (Variation ID: 201002). This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Lys559Glufs*38) have been determined to be pathogenic (PMID: 10090472, 15331604, 16449969; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The c.1548dupG pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a duplication of G at nucleotide position 1548, causing a translational frameshift with a predicted alternate stop codon (p.K517Efs*14). This mutation has been detected in several unrelated families with multiple endocrine neoplasia type 1 (MEN1) (Bartsch D et al. Dtsch. Med. Wochenschr., 1998 Dec;123:1535-40; Cardinal JW et al. J. Med. Genet., 2005 Jan;42:69-74). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.