ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.798+1G>A (rs794728652)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491531 SCV000579745 pathogenic Hereditary cancer-predisposing syndrome 2018-01-02 criteria provided, single submitter clinical testing The c.783+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the MEN1 gene. This alteration has been reported in two unrelated individuals with a clinical diagnosis of MEN1 (Morelli A et al. Eur. J. Endocrinol. 2000 Feb;142:131-7; Wen Z et al. Arq Bras Endocrinol Metabol. 2012 Apr;56:184-9). Furthermore, two different alterations at this same nucleotide position (c.783+1G>T, c.783+1G>C) have also been reported in patients with MEN1 (Giraud S et al. Am. J. Hum. Genet. 1998 Aug;63:455-67; Poncin J et al. Hum. Mutat. 1999;13:54-60). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506752 SCV000604214 pathogenic not specified 2017-02-05 criteria provided, single submitter clinical testing
Invitae RCV000697334 SCV000825936 pathogenic Multiple endocrine neoplasia, type 1 2019-08-05 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the MEN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with multiple endocrine neoplasia type 1 (PMID: 10664520, 22666734). This variant is also referred to as c.893+1G>A or IVS4+1 T>A in the literature. ClinVar contains an entry for this variant (Variation ID: 428081). Other variants affecting this nucleotide (c.783+1G>C and c.783+1G>T, also known as c.893+1G>C and c.893+1G>T in the literature) have been determined to be pathogenic (PMID: 9888389, 9683585). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). For these reasons, this variant has been classified as Pathogenic.
Genome Sciences Centre, British Columbia Cancer Agency RCV000515529 SCV000611149 likely pathogenic Metastatic pancreatic neuroendocrine tumours 2017-11-01 no assertion criteria provided research

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