Submissions for variant NM_001370259.2(MEN1):c.1072GAG[1] (p.Glu359del)

dbSNP: rs1060499971

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463375	SCV000541175	uncertain significance	Multiple endocrine neoplasia, type 1	2016-05-20	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). In summary, this is a rare in-frame deletion with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Experimental studies have not been reported for this single amino acid deletion; its functional consequence is uncertain. This variant has been reported in an individual affected with parathyroid tumors and pancreatic gastrinoma (PMID: 94633360). This sequence change deletes 3 nucleotides from exon 8 of the MEN1 mRNA (c.1075_1077delGAG). This leads to the deletion of 1 amino acid residue in the MEN1 protein (p.Glu359del) but otherwise preserves the integrity of the reading frame.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000463375	SCV000611873	benign	Multiple endocrine neoplasia, type 1	2018-03-28	criteria provided, single submitter	research	The MEN1 variant designated as NM_130799.2:c.1075_1077del (p.Glu359del) is classified as benign. In one observed family, multiple family members with the variant are unaffected by the multiple endocrine neoplasia constellation of symptoms, while one individual with a MEN1-associated cancer does not have the variant. Cosegregation analysis of this same observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 0.0001 to 1 that this allele explains cancer in the family (Thompson, et al., 2003, PMID:12900794). This likelihood ratio indicates strong evidence against pathogenicity as the variant does not co-segregate with reported multiple endocrine neoplasia symptoms in this family. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives a <0.1% probability of pathogenicity, which is consistent with a classification of benign. This variant is not predicted to alter MEN1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.