Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000491226 | SCV000579747 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-12-27 | criteria provided, single submitter | clinical testing | The p.H139D pathogenic mutation (also known as c.415C>G), located in coding exon 1 of the MEN1 gene, results from a C to G substitution at nucleotide position 415. The histidine at codon 139 is replaced by aspartic acid, an amino acid with some similar properties. This alteration has been previously identified in numerous individuals with multiple endocrine neoplasia type 1 (MEN1) (Stratakis et al. J Clin Endocrinol Metab. 2000 Dec; 85(12): 4776-80; Farrell WE et al. J Clin Endocrinol Metab. 2011 Nov;96(11):E1905-14; Ambry Internal Data). Functional studies have shown that this alteration leads to decreased MEN1 protein stability and abnormal transcriptional regulation of downstream targets (Shimazu S et al. Cancer Sci. 2011 Nov;102(11):2097-102; Agarwal SK et al. Hum Mol Genet.1997 Jul;6(7):1169-75; Canaff L et al. J Clin Endocrinol Metab. 2012 Feb;97(2):E282-91; Fang M et al. Mol. Cell. Biol., 2013 Jul;33:2635-47). Several other missense alterations at this codon (p.H139R, p.H139N, p.H139Q, p.H139P, p.H139Y) have also been identified in MEN1 probands (Martín-Campos JM et al. Diagn Mol Pathol. 1999 Dec;8(4):195-204; Cebrián A et al. J Med Genet. 2003 May;40(5):e72; Concolino P et al. Cancer Genet. 2016 Jan-Feb;209(1-2):36-41; Pardi E et al. PLoS One. 2017 Oct 16;12(10):e0186485; Carvalho RA et al. Eur J Endocrinol. 2018 Dec 1;179(6):391-407). Of note, this alteration is also designated c.525C>G in the published literature. Based on the available evidence, p.H139D is classified as a pathogenic mutation. |
| Labcorp Genetics |
RCV000018179 | SCV001585154 | pathogenic | Multiple endocrine neoplasia, type 1 | 2025-01-16 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 139 of the MEN1 protein (p.His139Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with MEN1-related conditions (PMID: 9215689, 21917868). ClinVar contains an entry for this variant (Variation ID: 16699). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MEN1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MEN1 function (PMID: 9989505, 12509449, 14508515, 15254225, 21264250, 21819486, 22090276, 22275377, 22327296). This variant disrupts the p.His139 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9215689, 30324798). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV004998101 | SCV005623341 | pathogenic | not provided | 2024-01-24 | criteria provided, single submitter | clinical testing | The MEN1 c.415C>G (p.His139Asp) variant has been reported in the published literature in affected individuals with multiple endocrine neoplasia type 1 (PMIDs: 9215689 (1997), 11134142 (2000), 15254225 (2004), 21917868 (2011), and 30324798 (2018)). Multiple functional studies have reported that this variant is damaging to protein function (PMIDs: 9989505 (1999), 12509449 (2003), 14508515 (2003), 15254225 (2004), 21264250 (2011), 21819486 (2011), 22090276 (2012), 22275377 (2012), 22327296 (2012), and 23648481 (2013)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. |
| OMIM | RCV000018179 | SCV000038458 | pathogenic | Multiple endocrine neoplasia, type 1 | 2000-12-01 | no assertion criteria provided | literature only |