owencqueen/cgbench_data huggingface dataset:
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: PS1 — Strong
Modification Type: Analogous Gene
Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:
Group 1: HRAS, NRAS, KRAS
 Group 2: MAP2K1, MAP2K2
Group 3: SOS1, SOS2
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: PS2 — Very Strong
Modification Type: Strength
≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.
Gene: SHOC2 (HGNC:15454)
Evidence Code: PS2 — Strong
Modification Type: None
De novo (paternity confirmed) in a patient with the disease and no family history.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific
Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: PS4 — Strong
Modification Type: General
≥5 independent occurrences.
Gene: SHOC2 (HGNC:15454)
Evidence Code: PS4 — Moderate
Modification Type: Strength
≥3 independent occurrences.
Gene: SHOC2 (HGNC:15454)
Evidence Code: PS4 — Supporting
Modification Type: Strength
≥1 independent occurrences.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: PM1 — Moderate
Modification Type: Analogous Gene
See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:
Group 1: HRAS, NRAS, KRAS
Group 2: MAP2K1, MAP2K2
Group 3: SOS1, SOS2
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: PM2 — Moderate
Modification Type: General
The variant must be completely absent from all population databases.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: PM4 — Moderate
Modification Type: None
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: PM5 — Strong
Modification Type: Strength
Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:
Group 1: HRAS, NRAS, KRAS
Group 2: MAP2K1, MAP2K2 Group 3: SOS1, SOS2
This rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.
≥2 different pathogenic missense changes seen before at same residue of missense change.
Gene: SHOC2 (HGNC:15454)
Evidence Code: PM5 — Moderate
Modification Type: Analogous Gene
Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:
Group 1: HRAS, NRAS, KRAS
Group 2: MAP2K1, MAP2K2 Group 3: SOS1, SOS2
This rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.
Gene: SHOC2 (HGNC:15454)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: SHOC2 (HGNC:15454)
Evidence Code: PM6 — Strong
Modification Type: Strength
≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.
Gene: SHOC2 (HGNC:15454)
Evidence Code: PM6 — Moderate
Modification Type: None
Confirmed de novo without confirmation of paternity and maternity.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: PP1 — Strong
Modification Type: Strength
Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.
≥7 informative meioses.
Gene: SHOC2 (HGNC:15454)
Evidence Code: PP1 — Moderate
Modification Type: Strength
Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.
≥5 informative meioses.
Gene: SHOC2 (HGNC:15454)
Evidence Code: PP1 — Supporting
Modification Type: General
Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: PP2 — Supporting
Modification Type: Disease-specific
PP2 is applicable to all RASopathy genes described and curated herein.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: PP3 — Supporting
Modification Type: None
Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
Gene: SHOC2 (HGNC:15454)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: SHOC2 (HGNC:15454)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.
Gene: SHOC2 (HGNC:15454)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: SHOC2 (HGNC:15454)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: BS2 — Strong
Modification Type: General
Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: BS3 — Strong
Modification Type: Disease-specific
Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: BS4 — Strong
Modification Type: General
Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.
Gene: SHOC2 (HGNC:15454)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: SHOC2 (HGNC:15454)
Evidence Code: BP1 — Supporting
Modification Type: Disease-specific
This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: BP2 — Supporting
Modification Type: None
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: SHOC2 (HGNC:15454)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: SHOC2 (HGNC:15454)
Evidence Code: BP3 — Supporting
Modification Type: None
In frame-deletions/insertions in a repetitive region without a known function.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: BP4 — Supporting
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: SHOC2 (HGNC:15454)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: SHOC2 (HGNC:15454)
Evidence Code: BP5 — Supporting
Modification Type: Variant found in a case with an alternate molecular basis for disease
Variant found in a case with an alternate molecular basis for disease.
Gene: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
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: SHOC2 (HGNC:15454)
Evidence Code: BP7 — Supporting
Modification Type: General
A synonymous (silent) 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.
This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.