Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000179.3(MSH6):c.3312dup(p.Gly1105TrpfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T1102T) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]
FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
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PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-47803552-C-CT is Pathogenic according to our data. Variant chr2-47803552-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 141667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf
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Pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Feb 22, 2022
The c.3312dupT pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a duplication of T at nucleotide position 3312, causing a translational frameshift with a predicted alternate stop codon (p.G1105Wfs*3). This mutation was detected in 1/537 French families tested for Lynch syndrome (Bonadona V et al. JAMA, 2011 Jun;305:2304-10). This mutation has been identified as germline in patients with glioblastoma and occurred de novo in at least one of these individuals (Forsström LM et al. J Neuropathol Exp Neurol, 2017 Oct;76:848-853; Wagener R et al. Eur J Hum Genet, 2021 08;29:1301-1311). 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. -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Aug 28, 2023
This variant causes a duplication of one nucleotide in exon 6 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in an individual affected with Lynch syndrome (PMID: 21642682) and in individuals affected with glioblastoma (PMID: 28922847, 33840814). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
not provided Pathogenic:2
Pathogenic, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
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Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Apr 26, 2023
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.3305_3306insT (p.1102-fs-insT); This variant is associated with the following publications: (PMID: 18269114, 24362816, 24728327, 34873480, 21642682, 34729042, 28922847, 28888541, 33840814) -
Lynch syndrome 5 Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Myriad Genetics, Inc.
Aug 22, 2023
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
This sequence change creates a premature translational stop signal (p.Gly1105Trpfs*3) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and gliobastomas (PMID: 21642682, 28922847). This variant is also known as c.3305_3306insT (p.1102-fs-insT). ClinVar contains an entry for this variant (Variation ID: 141667). For these reasons, this variant has been classified as Pathogenic. -