Submissions for variant NM_001370259.2(MEN1):c.652C>T (p.Arg218Trp)

dbSNP: rs794728620

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410087	SCV000488940	uncertain significance	Multiple endocrine neoplasia, type 1	2016-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410087	SCV000628092	pathogenic	Multiple endocrine neoplasia, type 1	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 218 of the MEN1 protein (p.Arg218Trp). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MEN1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 200976). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV001818447	SCV002067306	uncertain significance	not specified	2019-04-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362933	SCV002660838	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	The p.R218W variant (also known as c.652C>T), located in coding exon 2 of the MEN1 gene, results from a C to T substitution at nucleotide position 652. The arginine at codon 218 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was reported in a cohort of 54 individuals with a clinical or genetic diagnosis of MEN1, in an individual with primary hyperparathyroidism (Casey RT et al. Endocr Connect, 2017 Apr;6:151-158). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with MEN1-related disease (Ambry internal data). A review of MEN1 missense variants by the TENGEN network concluded this variant should be classified as a variant of uncertain significance based on proposed adjustments to the ACMGAMP interpretation framework (Romanet P et al. Hum. Mutat., 2019 06;40:661-674). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV000410087	SCV004018046	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.
All of Us Research Program, National Institutes of Health	RCV000410087	SCV004818543	uncertain significance	Multiple endocrine neoplasia, type 1	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 218 of the MEN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional and RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GenomeConnect, ClinGen	RCV000410087	SCV001338863	not provided	Multiple endocrine neoplasia, type 1		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 03-10-2018 by Lab or GTR ID Pathology Queensland. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.