owencqueen/cgbench_data huggingface dataset:
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: PVS1 — Very Strong
Modification Type: General recommendation
Nonsense/frameshift variant introducing Premature Termination Codon (PTC)
a 
 ≤ codon 798 in 
PMS2
. Refer to Appendix for details.


OR


Large genomic alterations
a
 of single or multi-exon size.


OR


Variants at IVS±1 or IVS±2​**
a,c 
 ** where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD. Not to be combined with PP3 and not to be used for a confirmed splice defect (see PVS1 for variants where patient mRNA assays indicate splicing aberration). If exon skipping or use of a cryptic splice site preserves reading frame and the altered region is critical to protein function
b
 then use PVS1_Strong. If exon skipping or use of a cryptic splice site disrupts reading frame and is NOT predicted to undergo NMD then use PVS1_Moderate.


OR


Variants where mRNA assays using RNA derived from patient constitutional biological samples indicate that the variant allele results in a splicing aberration (with evidence that the variant allele produces no full-length/reference transcript) leading to premature stop codon or in-frame deletion disrupting a functional domain
b
 or protein conformation. Splicing aberration must be confirmed in a minigene assay or an additional RNA assay from an independent laboratory if it is a non-canonical splice site variant.
Gene: PMS2 (HGNC:9122)
Evidence Code: PVS1 — Strong
Modification Type: General recommendation
Variants in the initiation codon of 
PMS2


OR 


Presumed by default in tandem duplication of ≥1 exon resulting in a frameshift before the last splice junction. This rule does not apply for variants that involve the UTR (i.e. exon 1 or last exon) and whole gene duplications.


OR


G>non-G at last base of exon if first 6 bases of the intron are not GTRRGT. If confirmed to cause a splice defect, then PVS1 should be used instead.


OR


Variants at IVS±1 or IVS±2​
a,c
 where exon skipping or use of a cryptic splice site preserves reading frame and the altered region is critical to protein function
b
. Not to be combined with PP3 and not to be used for a confirmed splice defect (see PVS1 for variants where patient mRNA assays indicate splicing aberration).
Gene: PMS2 (HGNC:9122)
Evidence Code: PVS1 — Moderate
Modification Type: Gene-specific
Nonsense/frameshift variant introducing premature termination codon between codons 799 & 862 in 
PMS2
. Refer to Appendix for details.
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: PS1 — Strong
Modification Type: General recommendation
A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic (not a predicted or confirmed splice defect).


OR


Variants affecting the same non-canonical splice nucleotide as a confirmed pathogenic splice variant with similar or worse splicing in silico prediction using SpliceAI.
Gene: PMS2 (HGNC:9122)
Evidence Code: PS1 — Moderate
Modification Type: General recommendation
A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change as a previously established Likely Pathogenic missense variant with normal RNA result*, and PM2_supporting is met.


*Otherwise, if the previously established Likely pathogenic missense variant truly is a splice defect, the new missense variant also has to be investigated on a functional level for RNA splicing.
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: PS2 — Very Strong
Modification Type: Disease-specific
≥ 4 
de novo
 points
Gene: PMS2 (HGNC:9122)
Evidence Code: PS2 — Strong
Modification Type: Disease-specific
2 or 3 
de novo
 points
Gene: PMS2 (HGNC:9122)
Evidence Code: PS2 — Moderate
Modification Type: Disease-specific
1 
de novo
 point
Gene: PMS2 (HGNC:9122)
Evidence Code: PS2 — Supporting
Modification Type: Disease-specific
0.5 
de novo
 points
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: PS3 — Strong
Modification Type: General recommendation
Calibrated functional assays with functional odds for Pathogenicity > 18.7
Gene: PMS2 (HGNC:9122)
Evidence Code: PS3 — Moderate
Modification Type: General recommendation
Calibrated functional assays with functional odds for pathogenicity >4.3 and <= 18.7


OR 


MMR function defect following functional assay flowchart*


OR 


Variants with monoallelic expression: complete loss of expression (<10% of wild-type in cDNA without puromycin) of the variant allele. Full-length transcript should be analysed with and without NMD block.
Gene: PMS2 (HGNC:9122)
Evidence Code: PS3 — Supporting
Modification Type: General recommendation
Calibrated functional odds for Pathogenicity >2.08 and <= 4.3
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: PM2 — Supporting
Modification Type: General recommendation
Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: PM3 — Very Strong
Modification Type: Disease-specific
≥ 4 points
Gene: PMS2 (HGNC:9122)
Evidence Code: PM3 — Strong
Modification Type: Disease-specific
≥ 2 and < 4 points
Gene: PMS2 (HGNC:9122)
Evidence Code: PM3 — Moderate
Modification Type: Disease-specific
≥1 and < 2 points
Gene: PMS2 (HGNC:9122)
Evidence Code: PM3 — Supporting
Modification Type: Disease-specific
= 0.5 points
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: PM5 — Moderate
Modification Type: General recommendation
Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level and not due to aberrant splicing. Only use PM5 if PP3 is supporting for the missense change. Use PM5_Supporting if other variant is Likely Pathogenic due to a missense alteration.
Gene: PMS2 (HGNC:9122)
Evidence Code: PM5 — Supporting
Modification Type: General recommendation
Missense change at an amino acid residue where a different missense change was classified as Likely Pathogenic on the protein level and not due to aberrant splicing. Only use PM5_Supporting if PP3 is supporting for the missense change. Use PM5 if other variant is Pathogenic due to a missense alteration.
Gene: PMS2 (HGNC:9122)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: PP1 — Strong
Modification Type: General recommendation
Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
h
 >18.7​ in ≥2 families.
Gene: PMS2 (HGNC:9122)
Evidence Code: PP1 — Moderate
Modification Type: General recommendation
Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio​
h
 >4.3 & ≤18.7.
Gene: PMS2 (HGNC:9122)
Evidence Code: PP1 — Supporting
Modification Type: General recommendation
Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
h
 >2.08 & ≤4.3.
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: PP3 — Moderate
Modification Type: General recommendation
Missense variant with HCI prior probability for pathogenicity >0.81 as per 
https://hci-priors.hci.utah.edu/PRIORS
Gene: PMS2 (HGNC:9122)
Evidence Code: PP3 — Supporting
Modification Type: General recommendation
Missense variant with “MAPP/PP2 Prior P” score  >0.68 & ≤0.81 from 
http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique
 


OR


Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.
Gene: PMS2 (HGNC:9122)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: PMS2 (HGNC:9122)
Evidence Code: PP4 — Strong
Modification Type: Disease-specific
≥3 independent CRC/Endometrial MSI-H tumors in ≥2 families using a standard panel of 5-10 markers​
g
 ​or tumor genome 
and/or
​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4_Strong. Independent tumors can be from the same patient/family.
Gene: PMS2 (HGNC:9122)
Evidence Code: PP4 — Moderate
Modification Type: Disease-specific
2 independent CRC/Endometrial MSI-H tumors using a standard panel of 5-10 markers​
g
 or tumor genome ​
and/or
​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4_Moderate.
Gene: PMS2 (HGNC:9122)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific
1 CRC/Endometrial MSI-H tumor using a standard panel of 5-10 markers​
g
 or tumor genome ​
and/or
​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4.
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: PMS2 (HGNC:9122)
Evidence Code: BA1 — Stand Alone
Modification Type: Gene-specific
GnomAD v4 Grpmax filtering allele frequency ≥ 0.0028 (0.28%) and variant is excluded as founder pathogenic variant.
Gene: PMS2 (HGNC:9122)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: PMS2 (HGNC:9122)
Evidence Code: BS1 — Strong
Modification Type: Gene-specific
GnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001 (0.01-0.1%) and variant is excluded as founder pathogenic variant.
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: BS2 — Strong
Modification Type: Disease-specific
Co-occurrence 
​in trans​
 with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 (or other LS cancer above the median age of onset for that cancer in LS​f​), and who has no previous or current evidence of clinical manifestations of CMMRD as per Aronson et al 2022 (Refer to 'Table for CMMRD diagnosis.pdf'). Confirmation of phase requires testing of parents or offspring.
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: BS3 — Strong
Modification Type: General recommendation
Calibrated functional assays with functional odds for Pathogenicity ≤ 0.05


OR


Synonymous substitutions and intronic variants with no associated mRNA aberration (either splicing or allelic imbalance) as determined by laboratory assays conducted with nonsense-mediated decay inhibition. Whenever abnormal transcripts are identified at similar levels in controls they will be considered naturally occurring isoforms and not mRNA aberrations.
Gene: PMS2 (HGNC:9122)
Evidence Code: BS3 — Supporting
Modification Type: General recommendation
Calibrated functional assays with functional odds for Pathogenicity >0.05 & ≤0.48


OR


Variant-specific proficient function in protein and mRNA-based lab assays as per MMR functional assay flowchart.
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: BS4 — Strong
Modification Type: General recommendation
Lack of co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
h
 <0.05​. 


*For multiple pedigrees, results are combined. Recommended segregation analysis tool: COOL (COsegregation OnLine) v2 
http://fengbj-laboratory.org/cool2/manual.html
Gene: PMS2 (HGNC:9122)
Evidence Code: BS4 — Supporting
Modification Type: General recommendation
Lack of co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
h
 >0.05 & ≤0.48.  


*with multiple pedigrees, results are combined. Recommended segregation analysis tool: COOL (COsegregation OnLine) v2 
http://fengbj-laboratory.org/cool2/manual.html
Gene: PMS2 (HGNC:9122)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: BP4 — Supporting
Modification Type: General recommendation
Missense variant with “MAPP/PP2 Prior P” score  <0.11 from 
http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique
 


OR


For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.
Gene: PMS2 (HGNC:9122)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: PMS2 (HGNC:9122)
Evidence Code: BP5 — Strong
Modification Type: Disease-specific
​≥ 4 tumors: CRC/Endometrial tumors with MSS ​and/or​ no ​loss of MMR protein expression​ ​and/or LS spectrum tumors
f
 with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation


OR


≥2 BRAF V600E (CRC only)/
MLH1
 methylation (in LS spectrum tumor only) with MSI-H/
MLH1
 loss.
Gene: PMS2 (HGNC:9122)
Evidence Code: BP5 — Supporting
Modification Type: Disease-specific
2 or 3 tumors: CRC/Endometrial tumors with MSS and/or no loss of MMR protein expression and/or LS spectrum tumors
f
 with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation.


OR 


1 BRAF V600E (Colon only)/
MLH1
 methylation (in LS spectrum tumor only) with MSI-H/
MLH1
 loss.
Gene: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
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: PMS2 (HGNC:9122)
Evidence Code: BP7 — Supporting
Modification Type: General recommendation
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.