chr11-64807649-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM5PP2PP3BS2
The NM_001370259.2(MEN1):c.686G>A(p.Arg229His) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,870 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. R229C) has been classified as Likely benign.
Frequency
Consequence
NM_001370259.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.686G>A | p.Arg229His | missense_variant | 4/10 | ENST00000450708.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.686G>A | p.Arg229His | missense_variant | 4/10 | 5 | NM_001370259.2 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251300Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135826
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461870Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727234
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 28, 2023 | This missense variant replaces arginine with histidine at codon 229 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with acromegaly and multiple adrenal adenomas (PMID: 15717658). This variant has been identified in 1/251300 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 17, 2022 | Variant summary: MEN1 c.686G>A (p.Arg229His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251300 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.686G>A has been reported in the literature in an individual with atypical Multiple Endocrine Neoplasia Type 1, but it was also present in two siblings of this individual that did not show any clinical evidence of disease (Pinna_2004). This report does not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 05, 2023 | The p.R229H variant (also known as c.686G>A), located in coding exon 3 of the MEN1 gene, results from a G to A substitution at nucleotide position 686. The arginine at codon 229 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in an individual with active acromegaly, associated to bilateral adenomatosis and Hürthle-cell thyroid neoplasia (Pinna G et al. J. Endocrinol. Invest., 2004 Jun;27:577-82). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at