11-64805122-C-T
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001370259.2(MEN1):c.1262G>A(p.Cys421Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,832 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 Likely pathogenic (★★).
Frequency
Consequence
NM_001370259.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.1262G>A | p.Cys421Tyr | missense_variant | Exon 9 of 10 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461832Hom.: 0 Cov.: 55 AF XY: 0.00000138 AC XY: 1AN XY: 727210
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Pathogenic:3
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This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 421 of the MEN1 protein (p.Cys421Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MEN1-related conditions (PMID: 15714081; Invitae). ClinVar contains an entry for this variant (Variation ID: 36523). 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%. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: MEN1 c.1262G>A (p.Cys421Tyr) results in a non-conservative amino acid change located in the Scaffolding protein domain of 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 250996 control chromosomes. c.1262G>A has been reported in the literature and observed at our laboratory in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (examples, Klein_2005, Simonds_2012, Shariq_2022, Christakis_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29122330, 15714081, 34183184, 21916912). ClinVar contains an entry for this variant (Variation ID: 36523). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
The MEN1 c.1262G>A;p.Cys421Tyr variant has been published in the literature in one individual with a clinical diagnosis of MEN1 (Klein 2005). Additionally, ARUP laboratories has detected this variant in an individual with a clinical diagnosis of MEN1. The variant is listed in the dbSNP variant database (rs386134249) and the ClinVar database (Variation ID: 36523), but is not listed in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The cysteine at position 421 is well conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Taken together, this variant is considered likely pathogenic. References: Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 7(2):131-8. -
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; This variant is associated with the following publications: (PMID: 17039269, 15714081, 17879353, 9989505, 34183184, 35428475) -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.C421Y variant (also known as c.1262G>A), located in coding exon 8 of the MEN1 gene, results from a G to A substitution at nucleotide position 1262. The cysteine at codon 421 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been observed in multiple individuals with a personal and/or family history that is consistent with multiple endocrine neoplasia type 1 (Ambry internal data). 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 supporting evidence, this variant is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at