Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000491393 | SCV000579653 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2016-04-21 | criteria provided, single submitter | clinical testing | The p.L338P variant (also known as c.1013T>C) is located in coding exon 6 of the MEN1 gene. This alteration results from a T to C substitution at nucleotide position 1013. The leucine at codon 338 is replaced by proline, an amino acid with similar properties. In a study of 200 unrelated Swedish index cases, this variant was reported in three affected members of one family. The proband was diagnosed with primary hyperparathyroidism with hyperplasia, an endocrine enteropancreatic gastrinoma, and an anterior pituitary tumor. The family members were diagnosed with hyperparathyriodism and insulinoma (Tham et al. J of Clinical Endocrinology & Metab. 2007. 92(9):3389-3395). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 7000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Gene |
RCV000494328 | SCV000581872 | likely pathogenic | not provided | 2017-05-08 | criteria provided, single submitter | clinical testing | The L338P variant in the MEN1 gene has previously been published in at least one individual with multiple endocrine neoplasia type 1 (Tham et al., 2007). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L338P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and is located within the region of interaction with FANCD2 (Uniprot). In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, L338P is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. |
| ARUP Laboratories, |
RCV000494328 | SCV005878001 | likely pathogenic | not provided | 2024-04-01 | criteria provided, single submitter | clinical testing | The MEN1 c.1013T>C; p.Leu338Pro variant (rs1114167480) is reported in the literature in individuals affected with multiple endocrine neoplasia, type 1 (Koyama 2022, Tham 2007). This variant was also found to segregate in family members affected with hyperparathyroidism and insulinoma (Koyama 2022, Tham 2007). This variant is also reported in ClinVar (Variation ID: 428016) and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.937). Based on available information, this variant is considered to be likely pathogenic. References: Koyama N et al. Multiple Endocrine Neoplasia Type 1 with Functional Parathyroid Cysts. Intern Med. 2022 Apr 15;61(8):1183-1188. PMID: 34645755. Tham E et al. Clinical testing for mutations in the MEN1 gene in Sweden: a report on 200 unrelated cases. J Clin Endocrinol Metab. 2007 Sep;92(9):3389-95. PMID: 17623761. |