ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1258C>T (p.Arg420Ter) (rs1060499974)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491295 SCV000579690 pathogenic Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000486722 SCV000567579 pathogenic not provided 2015-08-03 criteria provided, single submitter clinical testing The R415X nonsense variant in the MEN1 gene has been reported previously in association with multipleendocrine neoplasia type 1 (Lemmens et al., 1997; Filopanti et al., 2012; Nozières et al, 2014). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, anin vitro study has shown that menin protein expressing the R415X nonsense variant fails to inhibit cellgrowth (Nozières et al., 2014). Therefore, we interpret R415X as a pathogenic variant.
Invitae RCV000456454 SCV000541180 pathogenic Multiple endocrine neoplasia, type 1 2018-01-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg415*) in the MEN1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals and families with multiple endocrine neoplasia type 1 (PMID: 9215690, 11836268, 15670192, 17555499, 20833329, 25824098, 9329390). This variant is also known as c.1258C>T, p.R420X in the literature. ClinVar contains an entry for this variant (Variation ID: 403802). Loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). For these reasons, this variant has been classified as Pathogenic.

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