ClinVar Genomic variation as it relates to human health

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 555 of the MEN1 protein (p.Ser555Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with MEN1 (PMID: 9683585, 15254225). ClinVar contains an entry for this variant (Variation ID: 216134). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 15254225, 21819486). For these reasons, this variant has been classified as Pathogenic.

The p.S555N variant (also known as c.1664G>A), located in coding exon 9 of the MEN1 gene, results from a G to A substitution at nucleotide position 1664. The serine at codon 555 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in numerous families with MEN1-related tumors, including parathyroid, pituitary and endocrine pancreatic tumors (Giraud S et al. Am. J. Hum. Genet. 1998 Aug; 63(2):455-67; Wautot V et al. Hum. Mutat. 2002 Jul; 20(1):35-47; Tso AW et al. Clin. Endocrinol. (Oxf) 2003 Jul; 59(1):129-35). In addition, cell-based functional assays have demonstrated reduced stability and expression of the menin protein compared with wild-type (Yaguchi H et al. Mol. Cell. Biol. 2004 Aug; 24(15):6569-80; Shimazu S et al. Cancer Sci. 2011 Nov; 102(11):2097-102). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12112656, 9683585, 12807514]. Functional studies indicate this variant impacts protein function [PMID: 21819486, 22090276]. This variant is expected to disrupt protein structure [Myriad internal data].

Variant summary: MEN1 c.1664G>A (p.Ser555Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251390 control chromosomes. c.1664G>A has been reported in the literature in individuals affected with Multiple Endocrine Neoplasia Type 1 (Giraud_1998, Tso_2003, Wautot_2002). At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a decrease in expression levels (Yaguchi_2004, Shimazu_2011). The following publications have been ascertained in the context of this evaluation (PMID: 9683585, 21819486, 12807514, 12112656, 15254225). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.