ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.773C>T (p.Ser258Leu) (rs386134259)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491434 SCV000579696 uncertain significance Hereditary cancer-predisposing syndrome 2014-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,Other data supporting pathogenic classification
Invitae RCV000460727 SCV000541209 uncertain significance Multiple endocrine neoplasia, type 1 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 253 of the MEN1 protein (p.Ser253Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with primary hyperparathyroidism, and while additional family members are reported to have hypercalcemia and hyperparathyroidism, no segregation with disease was established (PMID: 17623761). This variant has been reported in an individual with pancreatic islet cell tumors (PMID: 20660572). ClinVar contains an entry for this variant (Variation ID: 201012). Experimental studies have shown that this missense change results in an unstable MEN1 protein that is rapidly degraded by the ubiquitin-proteasome pathway (PMID: 21819486). In summary, this variant is a rare missense change that has been reported in a family with phenotypes consistent with multiple endocrine neoplasia type 1. Also, experimental studies have shown that this variant has a deleterious effect on MEN1 protein expression and stability. However, in the absence of additional segregation and/or functional data, this variant has been classified as a Variant of Uncertain Significance.

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