rs143329068
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM5PP2BS2
The NM_001370259.2(MEN1):c.511C>T(p.Arg171Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R171Q) has been classified as Likely benign.
Frequency
Consequence
NM_001370259.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.511C>T | p.Arg171Trp | missense_variant | 3/10 | ENST00000450708.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.511C>T | p.Arg171Trp | missense_variant | 3/10 | 5 | NM_001370259.2 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000638 AC: 16AN: 250926Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135710
GnomAD4 exome AF: 0.0000499 AC: 73AN: 1461820Hom.: 0 Cov.: 33 AF XY: 0.0000413 AC XY: 30AN XY: 727204
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74314
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Uncertain:4Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 17, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 15, 2022 | The MEN1 c.511C>T (p.Arg171Trp) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant was observed in a Danish individual with primary hyperparathyroidism (PMID: 16563611). The in silico tool REVEL predicts a deleterious effect on protein function, however functional studies indicate that this variant does not significantly reduce menin expression compared to the wild-type (PMID: 21819486). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 20, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces arginine with tryptophan at codon 171 of the MEN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has reported that this variant does not impact MEN1 protein stability (PMID: 21819486). This variant has been reported in an individual affected with primary hyperparathyroidism (PMID: 16563611). This variant has been identified in 20/282320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 23, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband, multiple reports classify as non-pathogenic; ClinVar: 1 LB - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with primary hyperparathyroidism (Jger et al., 2006); Published functional studies demonstrated that this variant did not significantly impact MEN1 protein expression (Shimazu et al., 2011); This variant is associated with the following publications: (PMID: 25637381, 19068082, 17879353, 9989505, 16563611, 21819486) - |
Ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 25, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Hyperparathyroidism Benign:1
Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at