Submissions for variant NM_001370259.2(MEN1):c.673G>A (p.Gly225Arg)

dbSNP: rs1057521110

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000433003	SCV000521096	likely pathogenic	not provided	2016-10-04	criteria provided, single submitter	clinical testing	The G225R variant in the MEN1 gene has previously been reported in association with multiple endocrine neoplasia type 1 and familial isolated hyperparathyroidism (for examples, see Hai et al., 1999; Jager et al., 2006; Mizusawa et al., 2006). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G225R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and is located within the MEN1-FANC2 region of interaction (Jin et al., 2003). In silico analysis predicts G225R is probably damaging to the protein structure/function. Based on currently available evidence, G225R is a strong candidate for a pathogenic variant. However, the likelihood that it is a rare benign variant cannot be excluded.
Myriad Genetics, Inc.	RCV004022350	SCV004930915	likely pathogenic	Multiple endocrine neoplasia, type 1	2024-02-08	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10576763, 16817812, 16563611; Myriad internal data].
Ambry Genetics	RCV004943833	SCV005447362	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-10-19	criteria provided, single submitter	clinical testing	The p.G225R variant (also known as c.673G>A), located in coding exon 3 of the MEN1 gene, results from a G to A substitution at nucleotide position 673. The glycine at codon 225 is replaced by arginine, an amino acid with dissimilar properties. This variant was reported in multiple individuals who had clinical features of multiple endocrine neoplasia type 1 (MEN1) (Ambry internal data; Hai N et al. Eur J Endocrinol, 1999 Nov;141:475-80; Jäger AC et al. Mol Cell Endocrinol, 2006 Apr;249:123-32; Mizusawa N et al. Clin Endocrinol (Oxf), 2006 Jul;65:9-16). Of note, this alteration is also known as 783G>A in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.