ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1561dup (p.Arg521fs) (rs767319284)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000269197 SCV000329424 pathogenic not provided 2018-11-02 criteria provided, single submitter clinical testing This duplication of one nucleotide in MEN1 is denoted c.1546dupC at the cDNA level and p.Arg516ProfsX15 (R516PfsX15) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACCCCCC[dupC]GGAA. Using alternate nomenclature, this variant would be defined as MEN1 1561dupC, 1650insC, 1656dupC, 1657insC, 7766insC, or 7773insC. The duplication causes a frameshift which changes an Arginine to a Proline at codon 516, and creates a premature stop codon at position 15 of the new reading frame. Even though this frameshift occurs in the last exon of the gene, and nonsense-mediated decay is not expected to occur, it is significant since the last 95 amino acids are no longer translated correctly, and are replaced by 14 incorrect amino acids. This variant is predicted to cause loss of normal protein function through protein truncation. MEN1 c.1546dupC has been reported in at least one individual with familial isolated hyperparathyroidism and in many individuals with multiple endocrine neoplasia type 1 (Agarwal 1997, Bergman 2000, Warner 2004, Cardinal 2005, Pieterman 2012). This variant was reported to segregate with disease through five generations of a large Finnish MEN1 family (Kytola 2001). MEN1 c.1546dupC has been reported at a high frequency in patients with MEN1 in multiple populations and likely occurs as a result of a mutational hotspot (Giraud 1998, Kytola 2001, Ebeling 2004). In addition, in vitro functional studies show that this variant impairs nuclear localization of protein compared to wild-type (Ikeo 1999). Based on the currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000491230 SCV000579621 pathogenic Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000548407 SCV000628059 pathogenic Multiple endocrine neoplasia, type 1 2019-11-18 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 10 of the MEN1 mRNA (c.1546dupC), causing a frameshift at codon 516. This creates a premature translational stop signal in the last exon of the MEN1 mRNA (p.Arg516Profs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 80 amino acids of the MEN1 protein. This variant has been reported to segregate with disease in a large family affected with multiple endocrine neoplasia type 1 (MEN1) (PMID: 15635078) as well as in multiple other unrelated MEN1 familial cases (PMID: 9215689, 22470073, 24915123), and in sporadic MEN1 unrelated cases (PMID: 25291050, 21340156). In one of the sporadic cases the variant occurred de novo (PMID: 25291050). This variant is also known in the literature as c.1650insC, c.1561dup (p.Arg521fs), c.1561dupC, and c.1546dupC. ClinVar contains an entry for this variant (Variation ID: 279852). A different nucleotide change at the same position (c.1546delC) that results in a frameshift followed by a premature truncation (p.Arg516Glyfs*43) has been determined to be pathogenic (PMID: 9215689, 12112656, 12213668, 15670192, 17065424, 17853334, 23321498). This suggests that deletion of this region of MEN1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000548407 SCV000781725 pathogenic Multiple endocrine neoplasia, type 1 2016-11-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000269197 SCV001248412 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing

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