Submissions for variant NM_001370259.2(MEN1):c.1043T>A (p.Ile348Asn)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004703033	SCV005202334	likely pathogenic	Multiple endocrine neoplasia, type 1	2024-07-29	criteria provided, single submitter	clinical testing	Variant summary: MEN1 c.1043T>A (p.Ile348Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251448 control chromosomes. c.1043T>A has been reported in the literature in individuals affected with Multiple Endocrine Neoplasia Type 1 and segregated with disease in at-least two individuals from one family (example, Roijers_2000, Zhou_2006, Pieterman_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22470073, 10849016, 17013727). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004703033	SCV005836195	likely pathogenic	Multiple endocrine neoplasia, type 1	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 348 of the MEN1 protein (p.Ile348Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of multiple endocrine neoplasia type 1 (PMID: 10849016, 17013727). This variant is also known as c.1153T>A. 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.