owencqueen/cgbench_data huggingface dataset:
Gene: DICER1 (HGNC:17098)
Evidence Code: PVS1 — Original ACMG Summary
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Caveats:
 • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
 • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
 • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
 • Use caution in the presence of multiple transcripts.
Gene: DICER1 (HGNC:17098)
Evidence Code: PVS1 — Very Strong
Modification Type: Disease-specific,General recommendation
Follow SVI guidance, using DICER1-specific information.
Per the PVS1 workflow guidance provided in Tayoun et al. 2018 (PMID 30192042), the following will apply:




Nonsense or frameshift variants:


PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for DICER1 occurs at p.Pro1850.


PVS1_Moderate applies to variants resulting in protein truncation 3’ of this cutoff


Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies with the following exceptions:


Exon 10 SDS/SAS: PVS1_Strong (in-frame but exon includes >10% protein)


Exons 5, 15, 18, 22 SDS/SAS: PVS1_Moderate (in-frame and each <10% of protein)


Exon 27 SAS: PVS1_Moderate (final exon)


Exon 1: no criteria (non-coding)


Variants that disrupt the translation start site (p.M1?): no criteria applied given p.M1 is not highly conserved, there are three in-frame possible alternate start codons (p.Met11, p.Met17, p.Met24), and multiple lab cases of p.Met1? without
DICER1 phenotype.
SDS = splice donor site; SAS = splice acceptor site.
Refer to PS3 weight guidelines when a variant meets criterion for application of both PVS1 and PS3.
A disease-specific PVS1 decision tree incorporating the above bullets is also included at the end of this document as an additional curation tool.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS1 — Original ACMG Summary
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Example: Val->Leu caused by either G>C or G>T in the same codon.
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS1 — Strong
Modification Type: General recommendation
For same AA change, must confirm there is no difference in splicing using RNA data or in-silico modeling data (concordance of MaxEntScan and SpliceAI). For non-canonical intronic splicing variants at same nucleotide should have equal or worse splicing impact.
This rule code can only be used to compare variants asserted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS2 — Original ACMG Summary
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS2 — Very Strong
Modification Type: Strength
≥4 de novo points.
De novo points should be tallied using the simplified table for tallying
proband points and used to determine the applied strength of PS2, consistent
with SVI guidance. To avoid redundancy and increase consistency, the EP has
opted to drop PM6 and exclusively use PS2 for de novo evidence.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS2 — Strong
Modification Type: Strength
≥2 but less than 4 de novo points.
De novo points should be tallied using the simplified table for tallying
proband points and used to determine the applied strength of PS2, consistent
with SVI guidance. To avoid redundancy and increase consistency, the EP has
opted to drop PM6 and exclusively use PS2 for de novo evidence.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS2 — Moderate
Modification Type: General recommendation
≥1 but less than 2 de novo points.
De novo points should be tallied using the simplified table for tallying proband points and used to determine the applied strength of PS2, consistent with SVI guidance. To avoid redundancy and increase consistency, the EP has opted to drop PM6 and exclusively use PS2 for de novo evidence.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS2 — Supporting
Modification Type: Strength
≥0.5 but less than 1 de novo points.
De novo points should be tallied using the simplified table for tallying
proband points and used to determine the applied strength of PS2, consistent with SVI guidance. To avoid redundancy and increase consistency, the EP has opted to drop PM6 and exclusively use PS2 for de novo evidence.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific
RNA assay shows splicing impact that is out-of-frame, in-frame ≥193 residues, or in-frame with RNase IIIb disruption.
(PS3_Moderate if PVS1_Strong is applied).
This rule should be used and weighted appropriately for variants with functional evidence of a splicing impact and/or reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies. Do not apply PS3 at any strength if PVS1 is applied at full strength.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS3 — Moderate
Modification Type: Disease-specific,General recommendation
RNA assay shows in-frame splicing impact with change in protein length <193 residues AND RNase IIIb domain not disrupted.
This rule should be used and weighted appropriately for variants with functional evidence of a splicing impact and/or reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies. Do not apply PS3 at any strength if PVS1 is applied at full strength.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific,Strength
In vitro cleavage assay shows failure or severely reduced capacity to produce either 5p or 3p microRNAs from a premiRNA (positive and negative controls also performed). 
This rule should be used and weighted appropriately for variants with functional evidence of a splicing impact and/or reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies. Do not apply PS3 at any strength if PVS1 is applied at full strength.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS4 — Original ACMG Summary
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS4 — Strong
Modification Type: General recommendation
≥4 phenotype points.
Unrelated probands may contribute up to 1 point each based on phenotype (see Tables 2 & 3 in ruleset)
Caveats:




Do not apply PS4 if variant meets BA1/BS1 criteria.


Do not apply points for a phenotype in an individual with a likely pathogenic germline variant in a second gene that could have reasonably contributed to the phenotype (e.g. Wilms tumor in an individual with a P/LP WT1 variant).


Do not apply points for a proband whose tumor sequencing is consistent with a likely sporadic event (i.e. sequencing reveals a somatic, VCEPcurated, non-hotspot, likely pathogenic DICER1 variant in addition to a somatic hotspot variant and the germline variant under assessment). Of note, DICER1 tumors that consistently or occasionally follow a classical 2- hit hypothesis (i.e. LOF of both alleles) are exempt from this caveat. For example, identification of a somatic pathogenic non-hotspot DICER1 variant in pineoblastoma (PMID: 25022261), pituitary blastoma (PMID: 24839956), and lung cysts or cystic nephroma lacking mesenchymal cells (PMIDs: 25500911, 25978641) should not exclude the proband from PS4.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS4 — Moderate
Modification Type: Strength
2 – 3.5 phenotype points.
Unrelated probands may contribute up to 1 point each based on phenotype (see Tables 2 & 3 in ruleset)
Caveats:




Do not apply PS4 if variant meets BA1/BS1 criteria.


Do not apply points for a phenotype in an individual with a likely pathogenic germline variant in a second gene that could have reasonably contributed to the phenotype (e.g. Wilms tumor in an individual with a P/LP WT1 variant).


Do not apply points for a proband whose tumor sequencing is consistent with a likely sporadic event (i.e. sequencing reveals a somatic, VCEPcurated, non-hotspot, likely pathogenic DICER1 variant in addition to a somatic hotspot variant and the germline variant under assessment). Of note, DICER1 tumors that consistently or occasionally follow a classical 2- hit hypothesis (i.e. LOF of both alleles) are exempt from this caveat. For example, identification of a somatic pathogenic non-hotspot DICER1 variant in pineoblastoma (PMID: 25022261), pituitary blastoma (PMID: 24839956), and lung cysts or cystic nephroma lacking mesenchymal cells (PMIDs: 25500911, 25978641) should not exclude the proband from PS4.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS4 — Supporting
Modification Type: Strength
1 – 1.5 phenotype points.
Unrelated probands may contribute up to 1 point each based on phenotype (see Tables 2 & 3 in ruleset)
Caveats:




Do not apply PS4 if variant meets BA1/BS1 criteria.


Do not apply points for a phenotype in an individual with a likely pathogenic germline variant in a second gene that could have reasonably contributed to the phenotype (e.g. Wilms tumor in an individual with a P/LP WT1 variant).


Do not apply points for a proband whose tumor sequencing is consistent with a likely sporadic event (i.e. sequencing reveals a somatic, VCEPcurated, non-hotspot, likely pathogenic DICER1 variant in addition to a somatic hotspot variant and the germline variant under assessment). Of note, DICER1 tumors that consistently or occasionally follow a classical 2- hit hypothesis (i.e. LOF of both alleles) are exempt from this caveat. For example, identification of a somatic pathogenic non-hotspot DICER1 variant in pineoblastoma (PMID: 25022261), pituitary blastoma (PMID: 24839956), and lung cysts or cystic nephroma lacking mesenchymal cells (PMIDs: 25500911, 25978641) should not exclude the proband from PS4.
Gene: DICER1 (HGNC:17098)
Evidence Code: PM1 — Original ACMG Summary
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
Gene: DICER1 (HGNC:17098)
Evidence Code: PM1 — Moderate
Modification Type: Disease-specific
Putative missense variants at residues affecting metal ion-binding: codons p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813
Gene: DICER1 (HGNC:17098)
Evidence Code: PM1 — Supporting
Modification Type: Strength
Putative missense variants at residues in the RNase IIIb domain (p.Y1682 – p.S1846), besides the metal ion-binding residues (see PM1).
Gene: DICER1 (HGNC:17098)
Evidence Code: PM2 — Original ACMG Summary
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Caveat: Population data for indels may be poorly called by next generation sequencing.
Gene: DICER1 (HGNC:17098)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific,Strength
Allele frequency <0.000005 across gnomAD (non-cancer) with no more than one allele in any subpopulation and at least 20x coverage.
Gene: DICER1 (HGNC:17098)
Evidence Code: PM3 — Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase.
Gene: DICER1 (HGNC:17098)
Evidence Code: PM4 — Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: DICER1 (HGNC:17098)
Evidence Code: PM4 — Moderate
Modification Type: Disease-specific
In-frame indels with a residue within the RNase IIIb domain (p.Y1682 – p.S1846).
Gene: DICER1 (HGNC:17098)
Evidence Code: PM4 — Supporting
Modification Type: Strength
In-frame indels outside of the RNase IIIb domain (p.Y1682 – p.S1846) and repeat regions (p.D606-p.D609; p.E1418-p.E1420; p.E1422-p.E1425).
Gene: DICER1 (HGNC:17098)
Evidence Code: PM5 — Original ACMG Summary
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Example: Arg156His is pathogenic; now you observe Arg156Cys.
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Gene: DICER1 (HGNC:17098)
Evidence Code: PM5 — Moderate
Modification Type: General recommendation
Missense variant under evaluation should have equal or worse Grantham score. Splicing should be ruled out with either RNA data or agreement in splicing predictors (MaxEntScan and SpliceAI) that show no splicing effects. The other variant must be interpreted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply. This rule cannot be applied in combination with PM1 or PS1.
Gene: DICER1 (HGNC:17098)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: DICER1 (HGNC:17098)
Evidence Code: PP1 — Original ACMG Summary
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Note: May be used as stronger evidence with increasing segregation data.
Gene: DICER1 (HGNC:17098)
Evidence Code: PP1 — Strong
Modification Type: Strength
≥7 meioses across ≥2 families.
Phenotype-positive individuals should have high, moderate, or low-specificity phenotypes (see phenotype table). (Caveat: segregation with a single low-specificity phenotype across multiple individuals (e.g. familial Wilms tumor) does not fulfill PP1.)
Do not apply PP1 if variant meets BA1/BS1 criteria.
Gene: DICER1 (HGNC:17098)
Evidence Code: PP1 — Moderate
Modification Type: Strength
5 – 6 meioses across ≥1 family.
Phenotype-positive individuals should have high, moderate, or low-specificity phenotypes (see phenotype table). (Caveat: segregation with a single low-specificity
phenotype across multiple individuals (e.g. familial Wilms tumor) does not fulfill PP1.)
Do not apply PP1 if variant meets BA1/BS1 criteria.
Gene: DICER1 (HGNC:17098)
Evidence Code: PP1 — Supporting
Modification Type: General recommendation
3 – 4 meioses across ≥1 family.
Phenotype-positive individuals should have high, moderate, or low-specificity phenotypes (see phenotype table). (Caveat: segregation with a single low-specificity phenotype across multiple individuals (e.g. familial Wilms tumor) does not fulfill PP1.) 
Do not apply PP1 if variant meets BA1/BS1 criteria.
Gene: DICER1 (HGNC:17098)
Evidence Code: PP2 — Original ACMG Summary
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Gene: DICER1 (HGNC:17098)
Evidence Code: PP3 — Original ACMG Summary
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
Gene: DICER1 (HGNC:17098)
Evidence Code: PP3 — Supporting
Modification Type: Disease-specific
For missense variants, REVEL score ≥ 0.75 OR agreement in splicing predictors predict splicing effects. For splicing variants, concordance of MaxEntScan and SpliceAI.
Gene: DICER1 (HGNC:17098)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: DICER1 (HGNC:17098)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific
Somatic tumor testing identifies somatic hotspot second hit and no additional somatic LOF variants.
Tumor testing (PMID: 30311369) of a neoplasm with known DICER1 association in a proband who carries the germline variant under evaluation reveals the
following:




A previously reported somatic second hit of DICER1 in an RNase IIIb-disrupting “hotspot” codon (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or
p.E1813) AND 


Retention of the germline DICER1 variant under evaluation. 
PP4 is NOT applicable if:


The germline variant is a missense variant in one of the seven RNase IIIb “hotspot” codons (see PM1), OR


Somatic sequencing reveals additional DICER1 non-hotspot variants (could be consistent with sporadic tumorigenesis).
Gene: DICER1 (HGNC:17098)
Evidence Code: PP5 — Original ACMG Summary
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Gene: DICER1 (HGNC:17098)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: DICER1 (HGNC:17098)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Frequency >0.003 (0.3%) in gnomAD (non-cancer) subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.
Gene: DICER1 (HGNC:17098)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: DICER1 (HGNC:17098)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Frequency >0.0003 (0.03%) in gnomAD (non-cancer) subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.
Gene: DICER1 (HGNC:17098)
Evidence Code: BS2 — Original ACMG Summary
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Gene: DICER1 (HGNC:17098)
Evidence Code: BS2 — Strong
Modification Type: Disease-specific
40+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 40:1) 
OR 2+ observations of homozygosity in healthy individuals
OR 1+ observation(s) of homozygosity in a healthy individual with status confirmed by parental testing.
Gene: DICER1 (HGNC:17098)
Evidence Code: BS2 — Supporting
Modification Type: Disease-specific
10+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 10:1) 
OR 2+ observations of homozygosity in individuals lacking clinical information
Gene: DICER1 (HGNC:17098)
Evidence Code: BS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Gene: DICER1 (HGNC:17098)
Evidence Code: BS3 — Strong
Modification Type: Disease-specific
This rule should be used and weighted appropriately for variants with functional evidence of no splicing impact and/or no reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies.
For intronic or synonymous variants, no splicing impact observed via RNA assay. (Should be observed more than once.)
Gene: DICER1 (HGNC:17098)
Evidence Code: BS3 — Supporting
Modification Type: Disease-specific
This rule should be used and weighted appropriately for variants with functional evidence of no splicing impact and/or no reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies.
An in vitro cleavage assay must demonstrate the variant produces both 5p and 3p microRNAs from a pre-miRNA (positive and negative controls also performed). An example of an appropriate assay to which criteria could be applied is Wu et al. 2018 (PMID: 28862265).
Gene: DICER1 (HGNC:17098)
Evidence Code: BS4 — Original ACMG Summary
Lack of segregation in affected members of a family.
Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.
Gene: DICER1 (HGNC:17098)
Evidence Code: BS4 — Strong
Modification Type: General recommendation
Family members should be phenotype-positive (must be high- or moderatespecificity phenotype; see phenotype table), genotype-negative 1st, 2nd, or 3rd degree relatives of the proband.
Gene: DICER1 (HGNC:17098)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: DICER1 (HGNC:17098)
Evidence Code: BP2 — Original ACMG Summary
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Gene: DICER1 (HGNC:17098)
Evidence Code: BP2 — Supporting
Modification Type: Disease-specific
≥1 observation in trans with P/LP DICER1 variant or ≥3
observations in cis or phase unknown with 2+ different
P/LP DICER1 variants.
Gene: DICER1 (HGNC:17098)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: DICER1 (HGNC:17098)
Evidence Code: BP4 — Original ACMG Summary
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
Gene: DICER1 (HGNC:17098)
Evidence Code: BP4 — Supporting
Modification Type: Disease-specific
For missense variants, REVEL score < 0.50 and agreement in splicing predictors that no splicing effects are predicted. For synonymous/intronic/non-coding variants concordance of MaxEntScan and SpliceAI.
Gene: DICER1 (HGNC:17098)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: DICER1 (HGNC:17098)
Evidence Code: BP6 — Original ACMG Summary
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Gene: DICER1 (HGNC:17098)
Evidence Code: BP7 — Original ACMG Summary
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Gene: DICER1 (HGNC:17098)
Evidence Code: BP7 — Supporting
Modification Type: General recommendation
Silent variant
OR Intronic variant at or beyond +7 to -21 positions
OR Other intronic or non-coding variant if the variant is the reference nucleotide in ≥1 primate and/or ≥4 mammalian species.
Caveat: Variant must meet BP4 to apply BP7