Submissions for variant NM_001370259.2(MEN1):c.-20G>A

gnomAD frequency: 0.00158  dbSNP: rs386134244

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000480991	SCV000052856	benign	not specified	2018-09-12	criteria provided, single submitter	clinical testing	Variant summary: MEN1 c.-20G>A is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.00066 in 145114 control chromosomes, predominantly at a frequency of 0.006 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 288 fold of the estimated maximal expected allele frequency for a pathogenic variant in MEN1 causing Multiple Endocrine Neoplasia Type 1 phenotype (2.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.-20G>A in individuals affected with Multiple Endocrine Neoplasia Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Counsyl	RCV000030190	SCV000487916	likely benign	Multiple endocrine neoplasia, type 1	2015-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000480991	SCV000565124	likely benign	not specified	2017-12-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV002415435	SCV002730371	likely benign	Hereditary cancer-predisposing syndrome	2015-06-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Myriad Genetics, Inc.	RCV000030190	SCV004018039	uncertain significance	Multiple endocrine neoplasia, type 1	2023-04-17	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Breakthrough Genomics, Breakthrough Genomics	RCV004704817	SCV005211889	likely benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003914871	SCV004731668	likely benign	MEN1-related disorder	2019-05-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).