Submissions for variant NM_001370259.2(MEN1):c.542A>G (p.His181Arg)

dbSNP: rs1941861451

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001069023	SCV001234166	pathogenic	Multiple endocrine neoplasia, type 1	2022-09-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 862323). This variant is also known as p.His182Arg and c.557C>A (p.His186Arg). This missense change has been observed in individuals with clinical features of multiple endocrine neoplasia type 1 (PMID: 15714081, 22026581, 25824098). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 181 of the MEN1 protein (p.His181Arg).
GeneDx	RCV001574143	SCV001800904	likely pathogenic	not provided	2019-08-02	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; MEN1 H181R, also known as H186R, has been published in individuals with multiple endocrine neoplasia type 1 in the literature, but nomenclature discrepancies limit the ability to confirm that this is the specific variant in the current individual (Klein 2005, Belar 2012, Circelli 2015); Also known as c.652A>G or c.557A>G, p.H186R; This variant is associated with the following publications: (PMID: 25824098, 22026581, 15714081)
Ambry Genetics	RCV002348477	SCV002652906	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-04-27	criteria provided, single submitter	clinical testing	The p.H181R variant (also known as c.542A>G), located in coding exon 2 of the MEN1 gene, results from an A to G substitution at nucleotide position 542. The histidine at codon 181 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with a personal and/or family history that is consistent with or suspicious for MEN1-related disease (Klein RD et al. Genet Med, 2005 Feb;7:131-8; Belar O et al. Clin Endocrinol (Oxf), 2012 May;76:719-24; Circelli L et al. J Cell Mol Med, 2015 Jul;19:1735-41). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001069023	SCV003928656	pathogenic	Multiple endocrine neoplasia, type 1	2023-04-20	criteria provided, single submitter	clinical testing	Variant summary: MEN1 c.542A>G (p.His181Arg) results in a non-conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Another missense variant affecting this residue (p.His181Asp) has been classified as likely pathogenic by a ClinVar submitter. Five of five in-silico tools predict a damaging effect of the variant on protein function, and a computational analysis suggests it affects a salt bridge interaction (Biancaniello_2022). The variant was absent in 251316 control chromosomes (gnomAD). c.542A>G has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (Klein_2005, Belar_2012, Circelli_2012). These data indicate that the variant is very likely to be associated with disease. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.