11-64809695-G-C
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001370259.2(MEN1):c.415C>G(p.His139Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H139P) has been classified 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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.415C>G | p.His139Asp | missense_variant | 2/10 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.415C>G | p.His139Asp | missense_variant | 2/10 | 5 | NM_001370259.2 | ENSP00000394933 | P3 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 08, 2021 | Experimental studies have shown that this missense change affects MEN1 function (PMID: 9989505, 12509449, 14508515, 15254225, 21264250, 21819486, 22090276, 22275377, 22327296). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 16699). This missense change has been observed in individuals with MEN1-related conditions (PMID: 9215689, 21917868). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with aspartic acid at codon 139 of the MEN1 protein (p.His139Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant disrupts the p.His139 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9215689, 30324798). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2018 | The p.H139D pathogenic mutation (also known as c.415C>G), located in coding exon 1 of the MEN1 gene, results from a C to G substitution at nucleotide position 415. The histidine at codon 139 is replaced by aspartic acid, an amino acid with some similar properties. This alteration has been previously identified in numerous individuals with multiple endocrine neoplasia type 1 (MEN1) (Stratakis et al. J Clin Endocrinol Metab. 2000 Dec; 85(12): 4776-80; Farrell WE et al. J Clin Endocrinol Metab. 2011 Nov;96(11):E1905-14; Ambry Internal Data). Functional studies have shown that this alteration leads to decreased MEN1 protein stability and abnormal transcriptional regulation of downstream targets (Shimazu S et al. Cancer Sci. 2011 Nov;102(11):2097-102; Agarwal SK et al. Hum Mol Genet.1997 Jul;6(7):1169-75; Canaff L et al. J Clin Endocrinol Metab. 2012 Feb;97(2):E282-91; Fang M et al. Mol. Cell. Biol., 2013 Jul;33:2635-47). Several other missense alterations at this codon (p.H139R, p.H139N, p.H139Q, p.H139P, p.H139Y) have also been identified in MEN1 probands (Martín-Campos JM et al. Diagn Mol Pathol. 1999 Dec;8(4):195-204; Cebrián A et al. J Med Genet. 2003 May;40(5):e72; Concolino P et al. Cancer Genet. 2016 Jan-Feb;209(1-2):36-41; Pardi E et al. PLoS One. 2017 Oct 16;12(10):e0186485; Carvalho RA et al. Eur J Endocrinol. 2018 Dec 1;179(6):391-407). Of note, this alteration is also designated c.525C>G in the published literature. Based on the available evidence, p.H139D is classified as a pathogenic mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at