Submissions for variant NM_001370259.2(MEN1):c.1340T>C (p.Phe447Ser)

dbSNP: rs1941604532

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001238238	SCV001411037	likely pathogenic	Multiple endocrine neoplasia, type 1	2023-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 447 of the MEN1 protein (p.Phe447Ser). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MEN1 function (PMID: 12509449, 22090276). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MEN1 protein function. ClinVar contains an entry for this variant (Variation ID: 964090). This variant is also known as c.1355T>C (p.F452S ). This missense change has been observed in individuals with clinical features of multiple endocrine neoplasia type 1 and/or parathyroid gland tumors and/or pituitary adenoma (PMID: 9215689, 21916912, 22577108, 29497973). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001238238	SCV002766497	likely pathogenic	Multiple endocrine neoplasia, type 1	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: MEN1 c.1340T>C (p.Phe447Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250974 control chromosomes (gnomAD). c.1340T>C has been reported in the literature in individuals affected with Multiple Endocrine Neoplasia Type 1 (e.g. Agarwal_1997, Filopanti_2012). These data indicate that the variant may be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant retains the ability to interact with both RPA2 and JunD (Sukhodolets_2003), however during a 4-hour addition of cycloheximide to inhibit de novo protein synthesis the variant was unstable and degraded rapidly within 2 hours (Canaff_2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.