ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1277G>A (p.Cys426Tyr) (rs386134249)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000182419 SCV000604217 likely pathogenic not provided 2017-07-07 criteria provided, single submitter clinical testing The MEN1 c.1262G>A;p.Cys421Tyr variant has been published in the literature in one individual with a clinical diagnosis of MEN1 (Klein 2005). Additionally, ARUP laboratories has detected this variant in an individual with a clinical diagnosis of MEN1. The variant is listed in the dbSNP variant database (rs386134249) and the ClinVar database (Variation ID: 36523), but is not listed in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The cysteine at position 421 is well conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Taken together, this variant is considered likely pathogenic. References: Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 7(2):131-8.
Ambry Genetics RCV000491986 SCV000579623 likely pathogenic Hereditary cancer-predisposing syndrome 2014-09-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000182419 SCV000234763 likely pathogenic not provided 2018-04-24 criteria provided, single submitter clinical testing This variant is denoted MEN1 c.1262G>A at the cDNA level, p.Cys421Tyr (C421Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant was observed in at least one individual referred for MEN1 testing due to their personal and/or family history of MEN-associated lesions (Klein 2005). MEN1 Cys421Tyr was not observed in large population cohorts (Lek 2016). This variant 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 MEN1 Cys421Tyr to be a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000030196 SCV000052863 likely pathogenic Multiple endocrine neoplasia, type 1 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Invitae RCV000030196 SCV000541183 likely pathogenic Multiple endocrine neoplasia, type 1 2018-11-25 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 421 of the MEN1 protein (p.Cys421Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in a single family affected with multiple endocrine neoplasia type I (MEN1). However, not enough detail was provided to conclude whether this variant segregated with disease or not (PMID: 15714081). This variant has also been observed in three other individuals with bilateral parathyroid adenomas, two of whom had a family history suggestive of MEN1-related disease. ClinVar contains an entry for this variant (Variation ID: 36523). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change that is absent from the population and reported in several individuals affected with MEN1-related disease. This evidence indicates that the variant is pathogenic, but additional clinical and/or experimental evidence is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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