Submissions for variant NM_001370259.2(MEN1):c.35C>G (p.Pro12Arg)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002455181	SCV002614938	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-01-20	criteria provided, single submitter	clinical testing	The p.P12R variant (also known as c.35C>G), located in coding exon 1 of the MEN1 gene, results from a C to G substitution at nucleotide position 35. The proline at codon 12 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been observed in one individual with a pancreatic neuorendocrine tumor and hyperparathyroidism and another with pituitary adenoma and hyperparathyroidism (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003388109	SCV004099732	uncertain significance	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: MEN1 c.35C>G (p.Pro12Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 231760 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.35C>G in individuals affected with Multiple Endocrine Neoplasia Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29122330). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003517379	SCV004310799	likely pathogenic	Multiple endocrine neoplasia, type 1	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 12 of the MEN1 protein (p.Pro12Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of multiple endocrine neoplasia type 1 (internal data). ClinVar contains an entry for this variant (Variation ID: 1733068). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MEN1 protein function with a positive predictive value of 95%. This variant disrupts the p.Pro12 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9215689, 12509449, 15254225, 21264250, 21819486, 22090276; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx	RCV004779294	SCV005389917	likely pathogenic	not provided	2024-04-02	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21819486, 29122330, 21264250, 9989505, 15254225, 22090276, 9215689, 12509449)