chr11-64806312-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001370259.2(MEN1):c.969C>A(p.Tyr323Ter) variant causes a stop gained change involving the alteration of a non-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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y323Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001370259.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.969C>A | p.Tyr323Ter | stop_gained | 7/10 | ENST00000450708.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.969C>A | p.Tyr323Ter | stop_gained | 7/10 | 5 | NM_001370259.2 | P3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 07, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This premature translational stop signal has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9215689, 12791038, 22026581). ClinVar contains an entry for this variant (Variation ID: 403838). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr323*) in the MEN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Sep 03, 2014 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 13, 2022 | The p.Y323* pathogenic mutation (also known as c.969C>A), located in coding exon 6 of the MEN1 gene, results from a C to A substitution at nucleotide position 969. This changes the amino acid from a tyrosine to a stop codon within coding exon 6. This alteration has been identified in cohorts of patients with multiple endocrine neoplasia type 1 (MEN1) from Korea and Spain (Belar O et al. Clin. Endocrinol. (Oxf), 2012 May;76:719-24; Park JH et al. Clin. Genet. 2003 Jul;64:48-53). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at