ClinVar Genomic variation as it relates to human health

This sequence change creates a premature translational stop signal (p.Ala467Glyfs*59) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 144 amino acid(s) of the MEN1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with multiple endocrine neoplasia type 1 (MEN1) (PMID: 17853334). This variant is also known as 1509del14. ClinVar contains an entry for this variant (Variation ID: 657179). This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Gln554*) have been determined to be pathogenic (PMID: 11578300, 17158764, 17853334). 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.

Variant summary: MEN1 c.1400_1413del14 (p.Ala467GlyfsX59) 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 and HGMD. This variant is also known as c.1385_1398del14, p.Ala462GlyfsX59 in HGVS and 1509del14 in the literature. The variant was absent in 226168 control chromosomes (gnomAD). c.1400_1413del14 has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia (examples: Schaaf_2007 and Shariq_2022). These data indicate that the variant is associated with disease. One experimental study has demonstrated a truncation at the amino acid residue 527 (one amino acid downstream of the current truncation) abrogates the ability of MEN1 to bind DNA and repress cell proliferation (La_2004). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The c.1400_1413del14 pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a deletion of 14 nucleotides at nucleotide positions 1400 to 1413, causing a translational frameshift with a predicted alternate stop codon (p.A467Gfs*59). This alteration occurs at the 3' terminus of theMEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 144 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration, also referred to as 1509del14 in the literature, has been reported in several individuals with multiple endocrine neoplasia type 1 (MEN1) (Schaaf L et al. Exp Clin Endocrinol Diabetes, 2007 Sep;115:509-17; Manoharan J et al. World J Surg, 2017 08;41:2026-2032; Shariq OA et al. Surgery, 2022 01;171:77-87). Additionally, other truncating alterations downstream have been observed in individuals with a personal and/or family history that is consistent with MEN1-related disease (Ambry internal data).This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.