Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000129526 | SCV000184302 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-09-19 | criteria provided, single submitter | clinical testing | The p.R460* pathogenic mutation (also known as c.1378C>T), located in coding exon 9 of the MEN1 gene, results from a C to T substitution at nucleotide position 1378. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration occurs at the 3' terminus of theMEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 25% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data) and a significant portion of the protein is affected (Ambry internal data). This alteration has been identified in many unrelated patients and families with MEN1 (Agarwal SK et al. Hum Mol Genet.1997;6(7):1169-75; Matsuzaki LN et al. Clin Endocrinol (Oxf). 2004;60(1):142-3; Goroshi M et al. Fam. Cancer. 2016 Oct;15(4):617-24). In addition, this mutation has demonstrated expression levels at less than 20% compared to wild type in an in vitro study (Shimazu S et al. Cancer Sci. 2011 Nov;102(11):2097-102). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |
Gene |
RCV000182421 | SCV000234766 | pathogenic | not provided | 2019-08-01 | criteria provided, single submitter | clinical testing | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 9554741, 18753103, 29922966, 30339208, 10715991, 9215689, 11836268, 27212590, 22026581, 26767918, 26905068, 14678300, 27588171, 21819486, 28785839, 30342802) |
Eurofins Ntd Llc |
RCV000182421 | SCV000700503 | pathogenic | not provided | 2017-03-02 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000182421 | SCV000885689 | pathogenic | not provided | 2017-08-25 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000018172 | SCV000953567 | pathogenic | Multiple endocrine neoplasia, type 1 | 2024-01-30 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg460*) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 151 amino acid(s) of the MEN1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9215689, 14678300, 17879353, 18753103, 19461164). ClinVar contains an entry for this variant (Variation ID: 16692). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MEN1 function (PMID: 21819486). This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Arg516Glyfs*43) have been determined to be pathogenic (PMID: 17879353). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Clinical Genetics and Genomics, |
RCV000182421 | SCV001449957 | pathogenic | not provided | 2019-02-27 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000182421 | SCV002774386 | pathogenic | not provided | 2024-06-13 | criteria provided, single submitter | clinical testing | The MEN1 c.1378C>T (p.Arg460*) variant causes the premature termination of MEN1 protein synthesis. This variant has been reported in the published literature in multiple individuals and families affected with multiple endocrine neoplasia type 1 (MEN1) syndrome (PMID: 9215689 (1997), 9463336 (1998), 9540988 (1998), 9554741 (1998), 9681840 (1998), 9683585 (1998), 11836268 (2002), 14678300 (2004), 15635078 (2005), 17879353 (2008), 18753103 (2008), 19461164 (2009), 26905068 (2016), 35370956 (2022)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 21819486 (2011)). The frequency of this variant in the general population, 0.0000066 (1/152166 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. |
Myriad Genetics, |
RCV000018172 | SCV004189096 | pathogenic | Multiple endocrine neoplasia, type 1 | 2023-07-07 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. |
OMIM | RCV000018172 | SCV000038451 | pathogenic | Multiple endocrine neoplasia, type 1 | 1998-01-01 | no assertion criteria provided | literature only | |
Gene |
RCV000018172 | SCV002549164 | not provided | Multiple endocrine neoplasia, type 1 | no assertion provided | literature only |