Submissions for variant NM_001370259.2(MEN1):c.1667AGA[1] (p.Lys557del)

dbSNP: rs794728661

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182464	SCV000234809	likely pathogenic	not provided	2018-08-28	criteria provided, single submitter	clinical testing	This in-frame deletion of three nucleotides in MEN1 is denoted c.1670_1672delAGA at the cDNA level and p.Lys557del (K557del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAGA[delAGA]TGAA. This variant, also published as 1780delAGA using alternate nomenclature, was observed in several individuals with clinical histories consistent with multiple endocrine neoplasia type 1 (MEN1) (Giraud 1998, Cebri?n 2002, Wautot 2002, Cebri?n 2003). This variant was not observed in large population cohorts (Lek 2016). This deletion of a single Lysine amino acid is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this deletion to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001223385	SCV001395532	likely pathogenic	Multiple endocrine neoplasia, type 1	2024-07-16	criteria provided, single submitter	clinical testing	This variant, c.1670_1672del, results in the deletion of 1 amino acid(s) of the MEN1 protein (p.Lys557del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9683585, 22026581). This variant is also known as 1780delAGA. ClinVar contains an entry for this variant (Variation ID: 201023). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
PreventionGenetics, part of Exact Sciences	RCV003407673	SCV004109684	likely pathogenic	MEN1-related disorder	2023-06-01	criteria provided, single submitter	clinical testing	The MEN1 c.1670_1672delAGA variant is predicted to result in an in-frame deletion (p.Lys557del). This variant has been reported in individuals with multiple endocrine neoplasia (Table 1, referred to as 1780deAGA, Giraud et al. 1998. PubMed ID: 9683585; Table 1, referred to as 780delAGA, Wautot et al. 2002. PubMed ID: 12112656; Table 1, referred to as 1780del3, Cebrian et al, 2003. PubMed ID: 12746426; Table 1, Klein et al. 2005. PubMed ID: 15714081; Table 1, Belar et al. 2012. PubMed ID: 22026581). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has conflicting interpretations of likely pathogenic and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/201023/). This variant is interpreted as likely pathogenic.
Myriad Genetics, Inc.	RCV001223385	SCV004189063	likely pathogenic	Multiple endocrine neoplasia, type 1	2023-07-07	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12746426, 22026581, 9683585, 15714081]. This variant is expected to disrupt protein structure [Myriad internal data].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000182464	SCV004220026	uncertain significance	not provided	2022-05-13	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with multiple endocrine neoplasia type 1 (PMIDs: 9683585 (1998), 15714081 (2005), 22026581 (2012), and 23165842 (2012)). Based on the available information, we are unable to determine the clinical significance of this variant.