ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.789G>C (p.Gln263His) (rs374659656)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000463800 SCV000373099 likely benign Multiple endocrine neoplasia, type 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000379424 SCV000373100 uncertain significance Hyperparathyroidism 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000463800 SCV000541212 uncertain significance Multiple endocrine neoplasia, type 1 2019-12-29 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 258 of the MEN1 protein (p.Gln258His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs374659656, ExAC 0.003%). This variant has not been reported in the literature in individuals with MEN1-related disease. ClinVar contains an entry for this variant (Variation ID: 41855). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000034788 SCV000565127 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing This variant is denoted MEN1 c.774G>C at the cDNA level, p.Gln258His (Q258H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAC). This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). MEN1 Gln258His was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. MEN1 Gln258His occurs at a position that is conserved across species and is located in the region of interaction with FANCD2 (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MEN1 Gln258His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573824 SCV000673625 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-09 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034788 SCV000043287 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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