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This track hub displays variant interpretation data from the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) Variant Curation Expert Panel (VCEP) for Lynch syndrome genes: MLH1, MSH2, MSH6, and PMS2.
The hub contains eight complementary tracks that assist with variant classification according to the InSiGHT VCEP specifications:
This track displays clinically relevant functional domains for the four Lynch syndrome mismatch repair (MMR) genes as defined by the InSiGHT VCEP. While PM1 is not applicable to these genes, these domains are used in the PVS1 decision tree to determine whether a null variant affects a critical functional region.
Domains include:
This track displays HCI (Huntsman Cancer Institute) prior probability predictions for missense variants. These computational predictions, based on MAPP and PolyPhen-2 scores, are used to apply the PP3 (computational evidence supports pathogenicity) or BP4 (computational evidence supports benign) criteria.
This track displays ACMG/AMP allele frequency-based evidence codes derived from gnomAD v4.1 exome data. The frequency thresholds are gene-specific as defined by the InSiGHT VCEP specifications.
This track displays the PVS1 decision tree regions for each gene, which determine the appropriate strength of the PVS1 criterion for null variants (nonsense, frameshift, canonical splice site, initiation codon, single/multi-exon deletions). The regions are based on nonsense-mediated decay (NMD) predictions and critical functional regions.
This track displays variants in Lynch syndrome MMR genes that have been classified by the InSiGHT Variant Curation Expert Panel (VCEP) and submitted to ClinVar. All variants in this track have been "reviewed by expert panel" and represent the official InSiGHT VCEP classifications for Lynch syndrome genes.
Important note: This track specifically contains InSiGHT VCEP expert panel submissions to ClinVar, which represent the highest level of variant curation. These are distinct from other ClinVar submissions and reflect the consensus classification of the InSiGHT expert panel following ACMG/AMP guidelines with gene-specific modifications.
Note on gene symbols: A small number of variants (primarily large deletions and UTR variants) may display a neighboring gene symbol (e.g., FBXO11, AIMP2) instead of the expected MMR gene name. This occurs because ClinVar assigns gene symbols based on the genomic location of the variant, which may extend beyond the MMR gene boundaries. These variants are legitimate InSiGHT classifications for the MMR genes and the variant names correctly reference the MMR gene transcripts.
This track displays functional assay evidence from four published studies on Lynch syndrome mismatch repair (MMR) genes. Functional assay results are used to apply the PS3 (functional studies supportive of a damaging effect) or BS3 (functional studies show no damaging effect) criteria at various evidence strengths. The track combines data from:
Each variant is classified according to ACMG PS3/BS3 criteria using established thresholds. For the CIMRA assays (Drost 2018, Drost 2020, Rath 2022), the Odds for Pathogenicity (OddsPath) score is classified using Tavtigian thresholds. For the deep mutational scanning data (Jia 2021), the loss-of-function (LOF) score is used. Variants that fall between pathogenic and benign thresholds are classified as Indeterminate.
PMS2 has a closely related pseudogene, PMS2CL, located ~0.7 Mb centromeric on chromosome 7. PMS2CL shares ~98-99% sequence identity with PMS2 exons 9 and 11-15, which can lead to misalignment of short-read sequencing data and produce pseudogene-derived false-positive (or false-negative) PMS2 variant calls. This track highlights PMS2 exons with PMS2CL homology and the PMS2CL pseudogene region itself, alerting users that variants in these regions may benefit from additional orthogonal validation.
This track displays the curated PMS2 ClinVar variants from the "InSiGHT Curated Vars" track projected onto the equivalent positions on the PMS2CL pseudogene. It is intended to help analysts who detect a variant call on PMS2CL (from short-read NGS) recognize that it may actually correspond to a known classified PMS2 variant. Each item shows the PMS2CL n. notation, the equivalent PMS2 c. notation and classification, and the PMS2 genomic region for cross-reference.
| Color | Meaning |
|---|---|
| Fuchsia | Clinically relevant functional domain |
Mouseover displays: Domain name, Gene symbol, Transcript (NM accession), Amino acid location
| Color | ACMG Code | Meaning |
|---|---|---|
| Purple | PP3_moderate | HCI prior probability >0.81 (supports pathogenicity, moderate strength) |
| Light Purple | PP3_supporting | HCI prior probability 0.68-0.81 (supports pathogenicity, supporting strength) |
| Light Teal | BP4_supporting | HCI prior probability <0.11 (supports benign, supporting strength) |
Mouseover displays: HGVSc notation, HGVSp (protein change), ACMG code, MAPP/PP2 Prior probability value, Classification rule
| Color | ACMG Code | Meaning |
|---|---|---|
| Purple | PM2_supporting | Absent or extremely rare (<1 in 50,000) in gnomAD v4.1 |
| Teal | BS1 | Allele frequency too high for disorder (gene-specific thresholds; see Methods) |
| Dark Teal | BA1 | Stand-alone benign (gene-specific thresholds; see Methods) |
Mouseover displays: HGVSc notation, ACMG code, Classification rule
| Color | Region Type | ACMG Code | Meaning |
|---|---|---|---|
| Dark Red | NMD | PVS1 | Nonsense-mediated decay region – null variants eligible for full-strength PVS1 |
| Dark Red | CritRegion | PVS1 | Critical functional region – null variants eligible for full-strength PVS1 |
| Orange | FuncUnknown | PVS1_Moderate | Function unknown region – null variants eligible for PVS1 at moderate strength |
| Gray | PVS1_n.a. | PVS1_n.a. | PVS1 not applicable – region beyond functional relevance |
Mouseover displays: Region name, Gene symbol, Codon position rule, ACMG code
| Color | Classification | Meaning |
|---|---|---|
| Red | Pathogenic | Variant is pathogenic for Lynch syndrome |
| Pink | Likely pathogenic | Variant is likely pathogenic for Lynch syndrome |
| Dark Blue | Uncertain significance | Variant of uncertain significance (VUS) |
| Lime Green | Likely benign | Variant is likely benign |
| Green | Benign | Variant is benign |
Mouseover displays: Variant (HGVS notation), ClinVar ID with link, Classification, Date evaluated
| Color | Classification | Meaning |
|---|---|---|
| Dark Red | PS3_Strong | Strong evidence of pathogenicity (OddsPath >18.7 or LOF ≥0.4) |
| Red | PS3_Moderate | Moderate evidence of pathogenicity (OddsPath >4.3 and ≤18.7) |
| Pink | PS3_Supporting | Supporting evidence of pathogenicity (OddsPath >2.08 and ≤4.3) |
| Gray | Indeterminate | Score falls between pathogenic and benign thresholds (OddsPath >0.48 and ≤2.08, or LOF ≥0 and <0.4) |
| Lime Green | BS3_Supporting | Supporting evidence of benign effect (OddsPath >0.05 and ≤0.48) |
| Green | BS3_Strong | Strong evidence of benign effect (OddsPath ≤0.05 or LOF <0) |
Mouseover displays: HGVSc/HGVSp notation, Protein change, Classification, ClinVar ID with link (if available), OddsPath or LOF score, Paper reference with PubMed link
| Color | Caution Level | Meaning |
|---|---|---|
| Red | High | PMS2 exon with ≥99% homology to PMS2CL (exons 11-15) |
| Amber | Moderate | PMS2 exon with ~98% homology to PMS2CL (exon 9) |
| Green | Safe | PMS2 exon with no PMS2CL homology (exons 1-8, 10) |
| Gray | Pseudogene | PMS2CL pseudogene region |
Mouseover displays: Region name, Homology to PMS2CL, Caution level, and recommendation note
Items are colored by the classification of the equivalent PMS2 ClinVar variant, using the same color scheme as the InSiGHT Curated Variants track (red Pathogenic, pink Likely pathogenic, dark blue VUS, lime green Likely benign, green Benign).
Mouseover displays: PMS2CL n. notation, equivalent PMS2 c. notation, PMS2 classification, date evaluated, and the PMS2 genomic region (copy-paste to browser).
Protein domain boundaries were obtained from the InSiGHT VCEP specifications and mapped to genomic coordinates using the canonical transcripts:
HCI prior probabilities were obtained from the LOVD database and mapped to genomic coordinates. Classification thresholds follow the InSiGHT VCEP specifications:
Allele frequency data was obtained from gnomAD v4.1 exomes. The maximum population group allele frequency (grpmax AF) was used for classification according to InSiGHT VCEP thresholds:
PVS1 decision tree regions were defined based on the InSiGHT VCEP specifications, incorporating nonsense-mediated decay (NMD) predictions based on the 50-55 nucleotide rule, critical functional regions in the 3' portion of genes, and gene-specific codon boundaries:
Variant data was obtained from ClinVar via the NCBI E-utilities API. Only variants submitted by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) with "reviewed by expert panel" status were included. This represents the official InSiGHT VCEP classifications for Lynch syndrome genes.
Data summary:
Classification breakdown:
Coordinate mapping:
Unmapped variants:
Approximately 150 variants (9%) could not be mapped to hg38 coordinates, and 159 variants (9%) could not be mapped to hg19 coordinates. These are primarily large structural variants (deletions, duplications, complex rearrangements) where ClinVar does not provide precise genomic coordinates.
Data updates:
This track is automatically updated every Tuesday from ClinVar to capture new InSiGHT VCEP submissions. Updates are validated against a 10% item count tolerance before going live. See the makedoc for details on the update pipeline.
Functional assay data was extracted from the supplementary materials of four published studies. The data was mapped to genomic coordinates using the following canonical transcripts:
Variants with cDNA-level annotations (HGVSc) were mapped using the CDS position to determine single-nucleotide genomic coordinates. Variants with only protein-level annotations (HGVSp) were mapped to the 3-nucleotide codon span corresponding to the amino acid position. The name field uses the paper's original transcript version for traceability (e.g., NM_000249.3 for Drost 2018, NM_000249.4 for Rath 2022).
Classification thresholds:
For CIMRA assays (Drost 2018, Drost 2020, Rath 2022), the Odds for Pathogenicity (OddsPath) is classified using Tavtigian thresholds:
For the deep mutational scanning data (Jia 2021), the loss-of-function (LOF) score is classified as:
Data sources:
Data summary:
Classification breakdown:
See the makedoc for full build steps and the build scripts used to generate all tracks in this hub.
PMS2CL is the dominant pseudogene of PMS2, located at chr7:6,735,304-6,751,601 (hg38) / chr7:6,774,935-6,791,232 (hg19). It arose from an inverted duplication of the 3' half of PMS2 and shares high sequence identity with PMS2 exons 9 and 11-15. Active gene conversion between the two paralogs can produce hybrid alleles, and short-read sequencing reads from these exons can be mismapped between PMS2 and PMS2CL. PMS2CL lacks PMS2 exon 10, which is therefore commonly used as a gene-specific anchor for long-range PCR-based confirmation methods.
Per-exon homology classifications in this track are drawn from the published literature on PMS2/PMS2CL paralogy (see References: Clendenning 2006, Hayward 2007, van der Klift 2010, Vaughn 2011). Exon coordinates are queried from NCBI RefSeq transcript NM_000535.7. The track also includes one entry for the PMS2CL pseudogene region itself.
Curated PMS2 variants from the InSiGHT Curated Vars track were projected onto PMS2CL coordinates using the cDNA alignment between NM_000535.7 and NR_002217.1. The two transcripts are essentially gap-free in the homologous region with a near-constant offset (PMS2 c. = PMS2CL n. + 1060, with slight adjustments for exon 9 and one 1-bp indel in PMS2 exon 11). Projected items are placed at the genomic location of the equivalent PMS2CL nucleotides. Intronic variants and variants spanning exon boundaries with intronic positions are skipped, as are variants in PMS2 exons 1-8, 10, or beyond c.2798 (which have no PMS2CL counterpart). The build is part of the weekly ClinVar update.
The data underlying these tracks can be explored interactively using the UCSC Table Browser or downloaded from the track hub directory.
For the most current InSiGHT VCEP specifications, please visit the ClinGen CSpec Registry.
This track hub was created by the UCSC Genome Browser team in collaboration with the InSiGHT Variant Curation Expert Panel.
For questions about the data, please contact the InSiGHT VCEP coordinators.
Drost M, Tiersma Y, Thompson BA, Frederiksen JH, Keijzers G, Glubb D, Kathe S, Osinga J, Westers H, Pappas L et al. A functional assay-based procedure to classify mismatch repair gene variants in Lynch syndrome. Genet Med. 2019 Jul;21(7):1486-1496. PMID: 30504929; PMC: PMC7901556
Drost M, Tiersma Y, Glubb D, Kathe S, van Hees S, Calléja F, Zonneveld JBM, Boucher KM, Ramlal RPE, Thompson BA et al. Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome. Genet Med. 2020 May;22(5):847-856. PMID: 31965077; PMC: PMC7200593
Jia X, Burugula BB, Chen V, Lemons RM, Jayakody S, Maksutova M, Kitzman JO. Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. Am J Hum Genet. 2021 Jan 7;108(1):163-175. PMID: 33357406; PMC: PMC7820803
Rath A, Radecki AA, Rahman K, Gilmore RB, Hudson JR, Cenci M, Tavtigian SV, Grady JP, Heinen CD. A calibrated cell-based functional assay to aid classification of MLH1 DNA mismatch repair gene variants. Hum Mutat. 2022 Dec;43(12):2295-2307. PMID: 36054288; PMC: PMC9772141
Clendenning M, Hampel H, LaJeunesse J, Lindblom A, Lockman J, Nilbert M, Senter L, Sotamaa K, de la Chapelle A. Long-range PCR facilitates the identification of PMS2-specific mutations. Hum Mutat. 2006 May;27(5):490-5. PMID: 16619239
Hayward BE, De Vos M, Talseth-Palmer BA, Meldrum CJ, Watson JE, Phillips SM, Bowman R, Scott RJ, Bonthron DT. Extensive gene conversion at the PMS2 DNA mismatch repair locus. Hum Mutat. 2007 Apr;28(4):424-30. PMID: 17094075
van der Klift HM, Tops CM, Bik EC, Boogaard MW, Borgstein AM, Hansson KB, Ausems MG, Gomez Garcia E, Hes FJ, Hofstra RM, et al. Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients. Hum Mutat. 2010 May;31(5):578-87. PMID: 20186688
Vaughn CP, Robles J, Swensen JJ, Miller CE, Lyon E, Mao R, Bayrak-Toydemir P, Samowitz WS. Avoidance of pseudogene interference in the detection of 3' deletions in PMS2. Hum Mutat. 2011 Sep;32(9):1063-71. PMID: 21618646
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