owencqueen/cgbench_data huggingface dataset:
Gene: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
Evidence Code: PVS1 — Very Strong
Per modified CDH1 PVS1 decision tree.
Gene: CDH1 (HGNC:1748)
Evidence Code: PVS1 — Strong
Per modified CDH1 PVS1 decision tree.
Other CDH1 caveats:




Use PVS1_Strong as the default strength of evidence for canonical splice site variants and follow the site-specific recommendations in the splicing table. 


CDH1 Exonic deletions or tandem duplications of in-frame exons (exon 4,5,8,9,12,13,15).
Gene: CDH1 (HGNC:1748)
Evidence Code: PVS1 — Moderate
Per modified CDH1 PVS1 decision tree.
Other CDH1 caveats:




G to non-G variants disrupting the last nucleotide of an exon.


Canonical splice sites predicted or demonstrated experimentally to result in in-frame partial skipping/insertion (e.g., Exon 3 donor site).
Gene: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
Evidence Code: PS2 — Very Strong
≥Two patients meet the HDGC individual phenotype criteria w/ parental confirmation.
Gene: CDH1 (HGNC:1748)
Evidence Code: PS2 — Strong
One patient meets the HDGC individual phenotype criteria w/ parental confirmation.
Gene: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
Evidence Code: PS3 — Strong
RNA assay demonstrating abnormal out-of-frame transcripts.
Gene: CDH1 (HGNC:1748)
Evidence Code: PS3 — Moderate
RNA assay demonstrating abnormal in-frame transcript.
Gene: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
Evidence Code: PS4 — Very Strong
≥Sixteen families meet HDGC criteria.
Gene: CDH1 (HGNC:1748)
Evidence Code: PS4 — Strong
Four - Fifteen families meet HDGC criteria.
Gene: CDH1 (HGNC:1748)
Evidence Code: PS4 — Moderate
Two or three families meet HDGC criteria.
Gene: CDH1 (HGNC:1748)
Evidence Code: PS4 — Supporting
One family meets HDGC criteria.
Gene: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
Evidence Code: PM2 — Supporting
≤ One out of 100,000 alleles in gnomAD cohort; if present in ≥2 individuals within a subpopulation, must be present in ≤ One out of 50,000 alleles.
Gene: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
Evidence Code: PM4 — Moderate
Only apply to stop-loss variants
Variant example: CDH1 c.2647T>C (p.Ter883Glnext*29).
Gene: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
Evidence Code: PM5 — Supporting
PM5_supporting is applicable to nonsense and frameshift variants that are predicted/proved to undergo NMD or located upstream of the last known pathogenic truncating variant. Site-specific recommendations for the application of PM5_Supporting for canonical splicing variants.
Gene: CDH1 (HGNC:1748)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: CDH1 (HGNC:1748)
Evidence Code: PM6 — Very Strong
Four patients meet the HDGC individual phenotype criteria w/o parental confirmation.
Gene: CDH1 (HGNC:1748)
Evidence Code: PM6 — Strong
≥Two patients meet the HDGC individual phenotype criteria w/o parental confirmation.
Gene: CDH1 (HGNC:1748)
Evidence Code: PM6 — Moderate
One patient meets the HDGC individual phenotype criteria w/o parental confirmation
Gene: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
Evidence Code: PP1 — Strong
≥Seven informative meioses across ≥2 families.
Gene: CDH1 (HGNC:1748)
Evidence Code: PP1 — Moderate
Five-six informative meioses across ≥1 family.
Gene: CDH1 (HGNC:1748)
Evidence Code: PP1 — Supporting
Three-four informative meioses across ≥1 family.
Gene: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
Evidence Code: PP3 — Moderate
Variants affecting the same splice site as a well-characterized variant with similar or worse in silico/ RNA predictions.
Gene: CDH1 (HGNC:1748)
Evidence Code: PP3 — Supporting
At least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK).
Gene: CDH1 (HGNC:1748)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: CDH1 (HGNC:1748)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: CDH1 (HGNC:1748)
Evidence Code: BA1 — Stand Alone
MAF cutoff of 0.2%.
Gene: CDH1 (HGNC:1748)
Evidence Code: BS1 — Strong
MAF cutoff of 0.1%.
Gene: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
Evidence Code: BS2 — Strong
Variant seen in ≥10 individuals w/o GC, DGC, gSRC tumors, or LBC & whose families do not suggest HDGC.
Gene: CDH1 (HGNC:1748)
Evidence Code: BS2 — Supporting
Variant seen in ≥3 individuals w/o GC, DGC, SRC tumors, or LBC & whose families do not suggest HDGC.
Gene: CDH1 (HGNC:1748)
Evidence Code: BS3 — Strong
Functional RNA studies demonstrating no impact on transcript composition.
Gene: CDH1 (HGNC:1748)
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: CDH1 (HGNC:1748)
Evidence Code: BS4 — Strong
Per original ACMG/AMP guidelines.
Gene: CDH1 (HGNC:1748)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: CDH1 (HGNC:1748)
Evidence Code: BP2 — Strong
Variant observed in trans w/known pathogenic variant (phase confirmed) OR observed in the homozygous state in individual w/o personal &/or family history of DGC, LBC, or SRC tumors.
Gene: CDH1 (HGNC:1748)
Evidence Code: BP2 — Supporting
Variant is observed in cis (or phase is unknown) w/ a pathogenic variant
OR observed in the homozygous state in gnomAD.
Gene: CDH1 (HGNC:1748)
Evidence Code: BP4 — Supporting
Splicing predictions only. At least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK).
Gene: CDH1 (HGNC:1748)
Evidence Code: BP5 — Supporting
Per original ACMG/AMP guidelines.
Gene: CDH1 (HGNC:1748)
Evidence Code: BP7 — Supporting
Synonymous and intronic variants at or beyond +7 to -21 locations.