rs376872829
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM5PP2PP3BP6BS2
The NM_001370259.2(MEN1):c.526G>T(p.Ala176Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,018 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. A176P) has been classified as Pathogenic.
Frequency
Consequence
NM_001370259.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.526G>T | p.Ala176Ser | missense_variant | Exon 3 of 10 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251222Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135822
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461860Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727234
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
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 | Jan 11, 2024 | This missense variant replaces alanine with serine at codon 176 of the MEN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in 3 individuals or families affected with MEN1 (PMID: 30820182). A different missense variant at this codon, p.Ala176Pro, is considered disease-causing in ClinVar (variation ID 200975) and has been detected in a family affected with MEN1 (PMID: 9215689) and functional studies have shown the p.Ala176Pro variant to be unstable and exhibited loss of function in the binding and regulation of JunD and in homology-directed repair and response to DNA damage (PMID: 9989505, 11221882, 12509449, 22090276, 23648481). This variant has been identified in 5/251222 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2025 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 01, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals undergoing testing for Multiple Endocrine Neoplasia Type 1, with no phenotypic details provided (Isailovic 2019); This variant is associated with the following publications: (PMID: 31159747, 9989505, 30820182) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at