Criteria Specification Registry

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Criteria Specification

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Description : ACMG rules for RASopathy

Version : 1.0.0

PDF

RASopathy VCEP

Released

7/18/2017

05:00:00

Rules for SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF

Gene: SHOC2 (HGNC:15454) HGNC Name: SHOC2 leucine rich repeat scaffold protein Transcripts: Disease:

Gene: NRAS (HGNC:7989) HGNC Name: NRAS proto-oncogene, GTPase Transcripts: Disease:

Gene: RAF1 (HGNC:9829) HGNC Name: Raf-1 proto-oncogene, serine/threonine kinase Transcripts: Disease:

Gene: SOS1 (HGNC:11187) HGNC Name: SOS Ras/Rac guanine nucleotide exchange factor 1 Transcripts: Disease:

Gene: SOS2 (HGNC:11188) HGNC Name: SOS Ras/Rho guanine nucleotide exchange factor 2 Transcripts: Disease:

Gene: PTPN11 (HGNC:9644) HGNC Name: protein tyrosine phosphatase non-receptor type 11 Transcripts: Disease:

Gene: KRAS (HGNC:6407) HGNC Name: KRAS proto-oncogene, GTPase Transcripts: Disease:

Gene: MAP2K1 (HGNC:6840) HGNC Name: mitogen-activated protein kinase kinase 1 Transcripts: Disease:

Gene: HRAS (HGNC:5173) HGNC Name: HRas proto-oncogene, GTPase Transcripts: Disease:

Gene: RIT1 (HGNC:10023) HGNC Name: Ras like without CAAX 1 Transcripts: Disease:

Gene: MAP2K2 (HGNC:6842) HGNC Name: mitogen-activated protein kinase kinase 2 Transcripts: Disease:

Gene: BRAF (HGNC:1097) HGNC Name: B-Raf proto-oncogene, serine/threonine kinase Transcripts: Disease:

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment.
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong 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 Modification Type: Analogous Gene Moderate Supporting Not Applicable Comments: 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
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong ≥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. Modification Type: Strength Strong De novo (paternity confirmed) in a patient with the disease and no family history. Modification Type: None Moderate Supporting Not Applicable Comments: PS2_Very Strong: ≥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.
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong 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. Modification Type: Disease-specific Moderate Supporting Not Applicable Comments: 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.
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong ≥5 independent occurrences. Modification Type: General Moderate ≥3 independent occurrences. Modification Type: Strength Supporting ≥1 independent occurrences. Modification Type: Strength Not Applicable Comments: PS4: ≥5 independent occurrences PS4_Moderate: ≥3 independent occurrences PS4_Supporting: ≥1 independent occurrences
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate 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 Modification Type: Analogous Gene Supporting Not Applicable Comments: 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
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate The variant must be completely absent from all population databases. Modification Type: General Supporting Not Applicable Comments: The variant must be completely absent from all population databases.
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: This criterion is not applicable to the RASopathies.
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Stand Alone Very Strong Strong Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Modification Type: None Supporting Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong 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. Modification Type: Strength Moderate 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. Modification Type: Analogous Gene Supporting Not Applicable Comments: 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.
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. Stand Alone Very Strong Strong ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events. Modification Type: Strength Moderate Confirmed de novo without confirmation of paternity and maternity. Modification Type: None Supporting Not Applicable Comments: PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events. PS2_VeryStrong: ≥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.
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended. ≥7 informative meioses. Modification Type: Strength Moderate Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended. ≥5 informative meioses. Modification Type: Strength Supporting Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended. Modification Type: General Not Applicable Comments: PP1_Moderate: ≥5 informative meioses PP1_Strong: ≥7 informative meioses
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate Supporting PP2 is applicable to all RASopathy genes described and curated herein. Modification Type: Disease-specific Not Applicable Comments: PP2 is applicable to all RASopathy genes described and curated herein.
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Modification Type: None Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: This criterion is not applicable to the RASopathies. See PS4 criterion for proband counting options.
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. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information. Modification Type: Disease-specific Very Strong Strong Moderate Supporting Not Applicable Comments: An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information. Modification Type: Disease-specific Moderate Supporting Not Applicable Comments: An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong 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. Modification Type: General Moderate Supporting Not Applicable Comments: 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.
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong 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. Modification Type: Disease-specific Moderate Supporting Not Applicable Comments: 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.
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign. Modification Type: General Moderate Supporting Not Applicable Comments: Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Moderate Supporting 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. Modification Type: Disease-specific Not Applicable Comments: 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.
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate Supporting 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. Modification Type: None Not Applicable
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting In frame-deletions/insertions in a repetitive region without a known function. Modification Type: None Not Applicable
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate 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. Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong Moderate Supporting Variant found in a case with an alternate molecular basis for disease. Modification Type: Variant found in a case with an alternate molecular basis for disease Not Applicable
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. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate Supporting 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. Modification Type: General Not Applicable Comments: This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.