Submissions for variant NM_001370259.2(MEN1):c.721T>C (p.Cys241Arg)

dbSNP: rs1592649108

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816677	SCV000957195	likely pathogenic	Multiple endocrine neoplasia, type 1	2019-10-19	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys241 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been observed in individuals with MEN1-related conditions (PMID: 10576763, 12652570), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in several individuals affected with multiple endocrine neoplasia type 1 (PMID: 10090472, 20231234, Invitae). This variant is also known at c.831T>C in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 241 of the MEN1 protein (p.Cys241Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.
GeneDx	RCV002293487	SCV002586603	likely pathogenic	not provided	2022-10-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.831T>C; p.C246R; This variant is associated with the following publications: (PMID: 15281352, 15670192, 17879353, 9989505, 12874027, 20231234, 10090472)
Ambry Genetics	RCV002372308	SCV002670090	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-09-02	criteria provided, single submitter	clinical testing	The p.C241R variant (also known as c.721T>C), located in coding exon 3 of the MEN1 gene, results from a T to C substitution at nucleotide position 721. The cysteine at codon 241 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been identified in several patients with clinical features of multiple endocrine neoplasia type 1 (MEN1) (Mutch MG et al. Hum. Mutat., 1999;13:175-85; Ellard S et al. Clin Endocrinol (Oxf), 2005 Feb;62:169-75; White HD et al. QJM, 2010 May;103:337-45; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.