ClinVar Miner

Submissions for variant NM_001370259.2(MEN1):c.1664G>A (p.Ser555Asn) (rs863224527)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199920 SCV000253967 pathogenic Multiple endocrine neoplasia, type 1 2015-01-22 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 555 of the MEN1 protein (p.Ser555Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant has been reported in patients affected with MEN1 (PMID: 9683585, 15254225) but is not present in population databases. Experimental studies have shown that the mutant protein is targeted for rapid proteasome degradation and the expression of the mutant protein is diminished (PMID: 21819486, 15254225). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000491766 SCV000579740 likely pathogenic Hereditary cancer-predisposing syndrome 2016-05-18 criteria provided, single submitter clinical testing The p.S555N variant (also known as c.1664G>A), located in coding exon 9 of the MEN1 gene, results from a G to A substitution at nucleotide position 1664. The serine at codon 555 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in numerous families withMEN1-relatedtumors, including parathyroid, pituitary and endocrine pancreatic tumors(GiraudS etal.Am. J.Hum. Genet.1998 Aug; 63(2):455-67;WautotV et al.Hum.Mutat.2002 Jul; 20(1):35-47;Tso AW et al.Clin.Endocrinol. (Oxf)2003 Jul; 59(1):129-35). In addition,cell-based functional assays have demonstrated reduced stability and expression of themeninprotein compared with wild-type (YaguchiH et al.Mol. Cell.Biol.2004 Aug; 24(15):6569-80;ShimazuS et al.Cancer Sci.2011 Nov; 102(11):2097-102).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 7000alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Based on the majority of available evidence to date, this variant is likely to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507111 SCV000604203 likely pathogenic not specified 2017-01-05 criteria provided, single submitter clinical testing
Mendelics RCV000199920 SCV000838447 likely pathogenic Multiple endocrine neoplasia, type 1 2018-07-02 criteria provided, single submitter clinical testing

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