rs386134259
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_001370259.2(MEN1):c.758C>T(p.Ser253Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S253W) has been classified as Pathogenic.
Frequency
Consequence
NM_001370259.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.758C>T | p.Ser253Leu | missense_variant | 4/10 | ENST00000450708.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.758C>T | p.Ser253Leu | missense_variant | 4/10 | 5 | NM_001370259.2 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461840Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727212
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Pathogenic:3Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 253 of the MEN1 protein (p.Ser253Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of multiple endocrine neoplasia type 1 (PMID: 17623761, 20660572; Invitae). ClinVar contains an entry for this variant (Variation ID: 201012). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MEN1 function (PMID: 21819486). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS) | Apr 10, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 30, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 21, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2022 | Published functional studies demonstrate a damaging effect: decreased protein expression and stability (Shimazu 2011); Observed in individuals with MEN1-related tumors referred for testing at GeneDx and in published literature (Tham 2007, Erlic 2010, Raj 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.868C>T; p.S258L; This variant is associated with the following publications: (PMID: 10931084, 17623761, 17065424, 17879353, 20660572, 24265153, 26269718, 30687805, 30869828, 12874027, 21819486) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 13, 2021 | The p.S253L variant (also known as c.758C>T), located in coding exon 3 of the MEN1 gene, results from a C to T substitution at nucleotide position 758. The serine at codon 253 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with MEN1-related disease (Ambry internal data). This alteration has also been reported in two unrelated families with hyperparathyroidism (HPT) (Tham E et al. J Clin Endocrinol Metab. 2007 Sep;92(9):3389-95; Potorac I et al. Annales d'Endocrinologie 2015 Sept;76(4) 486) and in an affected German patient listed in the international Neuroendocrine Tumor Registry (Erlic Z et al Endocr Relat Cancer. 2010 Oct 5;17(4):875-83). Based on internal structural analysis, this alteration is anticipated to destabilize the structure of menin (Murai MJ et al. J. Biol. Chem., 2011 Sep;286:31742-8; Huang J et al. Nature, 2012 Feb;482:542-6). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at