PMS2 c.23+32dup, p.?

Rule

For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.

Evidence considered

• SpliceAI maximum delta score = 0.02.
• PMS2 VCEP BP4 for intronic variants requires SpliceAI delta score <= 0.1.

Sources

Rule

A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.

Evidence considered

• Variant nomenclature places the change at intronic position +32.
• PMS2 VCEP BP7 applies to intronic variants at or beyond +7.

Sources

Rule

PMS2 VCEP PVS1 applies to specified null variants or to variants with qualifying constitutional RNA evidence showing a pathogenic splicing aberration.

Evidence considered

• PVS1 gene gate is eligible for PMS2 loss of function.
• Generic PVS1 scaffold indicates this variant is not in a default null-variant bucket.
• SpliceAI maximum delta score = 0.02
• without evidence of a major splice defect.

Still missing

• No constitutional RNA study demonstrating a pathogenic splice defect was identified.

Sources

Rule

Absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4 dataset.

Evidence considered

• gnomAD v4.1 total AF = 5.0248e-05 (81/1612004).
• PMS2 VCEP PM2 threshold requires AF < 0.00002.
• gnomAD v2.1 total AF was lower at 7.99226e-06
• but the PMS2 VCEP rule specifies the v4 dataset.

Sources

Rule

Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.

Evidence considered

• SpliceAI maximum delta score = 0.02.
• PMS2 VCEP PP3 for non-canonical splice variants requires SpliceAI delta score >= 0.2.

Sources

Rule

GnomAD v4 Grpmax filtering allele frequency ≥ 0.0028 (0.28%) and variant is excluded as founder pathogenic variant.

Evidence considered

• gnomAD v4.1 grpmax FAF = 5.301e-05.
• PMS2 VCEP BA1 threshold = 0.0028.

Sources

Rule

GnomAD v4 Grpmax filtering allele frequency ≥ 0.00028 and < 0.0028 (0.028-0.28%) and variant is excluded as founder pathogenic variant.

Evidence considered

• gnomAD v4.1 grpmax FAF = 5.301e-05.
• PMS2 VCEP BS1 threshold requires grpmax FAF >= 0.00028 and < 0.0028.

Sources

Rule

Variants affecting the same non-canonical splice nucleotide as a confirmed Pathogenic splice variant with similar or worse splicing in silico prediction using SpliceAI, or the analogous Likely Pathogenic rule for PS1_Moderate.

Evidence considered

• PMS2 VCEP PS1 requires a previously established pathogenic or likely pathogenic variant at the same non-canonical splice nucleotide with similar or worse SpliceAI prediction.
• No exact match for this variant was identified in the reviewed pilot variant spreadsheet.

Still missing

• Variant-level evidence for previously established pathogenic or likely pathogenic variants at the same non-canonical splice nucleotide was not identified.

Sources

Rule

De novo points-based PMS2 VCEP rule.

Evidence considered

• PMS2 VCEP PS2 requires de novo points supported by tumor findings and parental confirmation.

Still missing

• No confirmed de novo observations were identified.
• No qualifying tumor data linked to a de novo occurrence were identified.

Sources

Rule

Calibrated functional assays with pathogenic odds above threshold, MMR function defect by flowchart, or qualifying monoallelic expression loss.

Evidence considered

• PMS2 VCEP PS3 requires calibrated functional evidence or qualifying RNA evidence.

Still missing

• No variant-specific protein functional assay data were identified.
• No variant-specific constitutional RNA data showing loss of normal transcript were identified.

Sources

Rule

Points-based in trans observations under the PMS2 VCEP PM3 framework.

Evidence considered

• PMS2 VCEP PM3 requires points from qualifying in trans observations.

Still missing

• No phase-confirmed in trans observations were identified.
• No CMMRD-related case evidence relevant to PM3 scoring was identified.

Sources

Rule

Missense change at an amino acid residue where a different missense change was classified by this VCEP as pathogenic or likely pathogenic on the protein level and not due to aberrant splicing.

Evidence considered

• PMS2 VCEP PM5 is a missense same-residue rule.

Sources

Rule

Co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio exceeding the PP1 thresholds.

Evidence considered

• PMS2 VCEP PP1 requires segregation evidence quantified by Bayes likelihood ratio.

Still missing

• No pedigree-based segregation evidence or Bayes likelihood ratios were identified.

Sources

Rule

CRC/endometrial MSI-H and/or loss of MMR protein expression consistent with variant location.

Evidence considered

• PMS2 VCEP PP4 requires qualifying MSI-H and/or IHC evidence.

Still missing

• No CRC or endometrial tumor MSI data were identified.
• No immunohistochemistry data showing protein loss consistent with PMS2 were identified.

Sources

Rule

Co-occurrence in trans with a known pathogenic sequence variant in the same gene in a patient meeting the PMS2 VCEP BS2 clinical conditions.

Evidence considered

• PMS2 VCEP BS2 requires in trans co-occurrence with a known pathogenic PMS2 variant plus clinical context excluding CMMRD.

Still missing

• No qualifying in trans co-occurrence data were identified.
• No clinical information was identified to evaluate absence of CMMRD features under the VCEP rule.

Sources

Rule

Calibrated functional assays with benign odds thresholds, no associated mRNA aberration in qualifying RNA assays, or proficient function in protein and mRNA assays.

Evidence considered

• PMS2 VCEP BS3 requires calibrated benign functional evidence or qualifying RNA evidence showing no aberration.

Still missing

• No variant-specific constitutional RNA assay showing no aberrant transcript was identified.
• No variant-specific functional assay showing proficient function was identified.

Sources

Rule

Lack of co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio within the BS4 thresholds.

Evidence considered

• PMS2 VCEP BS4 requires quantified lack-of-segregation evidence.

Still missing

• No pedigree-based lack-of-segregation evidence or Bayes likelihood ratios were identified.

Sources

Rule

Tumor evidence inconsistent with the gene demonstrating genetic variation, or qualifying BRAF/MLH1 methylation evidence under the PMS2 VCEP rule.

Evidence considered

• PMS2 VCEP BP5 requires specific tumor-based evidence inconsistent with PMS2-associated disease.

Still missing

• No qualifying MSS or discordant MMR protein expression tumor data were identified.
• No BRAF V600E or MLH1 methylation evidence relevant to this rule was identified.

Sources