Variant classification summary

NM_000535.7:c.353+7C>A

PMS2 · NP_000526.2:p.? · NM_000535.7

GRCh37: chr7:6043314 G>T · GRCh38: chr7:6003683 G>T

Gene: PMS2 Transcript: NM_000535.7

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.?

gnomAD AF

6.740025099853472e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 Supporting: the gnomAD v4.1 allele frequency is 6.74003e-06, below the VCEP cutoff of 0.00002.

2

BP4 Supporting: SpliceAI's maximum delta score is 0.014, below the VCEP no-splicing-impact threshold of 0.1.

3

BP7 Supporting: c.353+7 lies within the VCEP's included intronic boundary at or beyond +7.

Final determination: Under Rule19 of the PMS2 VCEP Version 2.0 framework, at least two benign Supporting criteria are sufficient for a Likely Benign classification; PM2, BP4, and BP7 meet this requirement.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: c.353+7C>A is outside the VCEP's GT-AG 1,2 PVS1 splice-site scope, and SpliceAI's maximum delta score is 0.01.	cspec vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr spliceai
PS1	Not assessed	Not assessed: SpliceAI maximum delta is 0.014, but no qualifying VCEP-established pathogenic comparator at c.353+7 with a comparable score was identified.	cspec spliceai
PS2	Not assessed	Not assessed: no proband-parent testing, maternity or paternity confirmation, LS-spectrum tumor result, or de novo point assignment is provided.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay result, functional odds, or demonstrated MMR defect is available for PMS2 c.353+7C>A.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PS4	N/A	Not applicable: the PMS2 VCEP excludes PS4 proband-counting classification because tumor IHC evidence is evaluated through PP4.	cspec PMID:25741868 PMID:34012068 PMID:34043773
PM1	N/A	Not applicable: the PMS2 VCEP specification explicitly marks PM1 as Not Applicable for this framework.	cspec vcep_mmr_functional_domains
PM2	Met	Met at Supporting: gnomAD v4.1 AF is 6.74003e-06, below the VCEP PM2 cutoff of 0.00002.	gnomad_v4 gnomad_v2 vcep_vcep_pilot_variants_mmr
PM3	Not assessed	Not assessed: no pathogenic PMS2 partner variant, CMMRD features, or phase evidence is available to assign the VCEP's 0.5-point phase-unknown or 1.0-point trans weight.	cspec
PM4	N/A	Not applicable: the PMS2 VCEP explicitly marks PM4 Not Applicable, and this intronic variant has no evaluable protein-length change.	cspec
PM5	N/A	Not applicable: c.353+7C>A has an unknown protein consequence and is not a missense change at an amino-acid residue.	cspec pm5_candidates
PM6	N/A	Not applicable: the PMS2 VCEP explicitly marks PM6 as not applicable in its Version 2.0 specification.	cspec
PP1	Not assessed	Not assessed: no pedigree segregation data or combined Bayes likelihood ratio is provided for comparison with the VCEP thresholds of >2.08, >4.3, or >18.7.	cspec
PP2	N/A	Not applicable: PP2 is explicitly excluded by the PMS2 VCEP specification, and this variant has an unknown protein consequence.	cspec
PP3	Not met	Not met: SpliceAI maximum delta score 0.014 is below the VCEP PP3 splice-defect threshold of >=0.2.	cspec spliceai vcep_hci_priors_pms2
PP4	Not assessed	Not assessed: no patient-level CRC/endometrial MSI-H, tumor-genome, or PMS2-loss evidence is available to meet the PP4 tumor threshold.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
PP5	N/A	Not applicable: the PMS2 VCEP prohibits PP5, regardless of the exact variant's likely-benign ClinVar reports.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 4.7e-06, far below the VCEP BA1 threshold of 0.0028.	gnomad_v4 vcep_vcep_pilot_variants_mmr
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 4.7e-06, below the VCEP BS1 lower threshold of 0.00028.	gnomad_v4 vcep_vcep_pilot_variants_mmr
BS2	Not assessed	Not assessed: no qualifying in-trans co-occurrence, cancer-age, CMMRD, or phase-confirmation evidence is available.	cspec
BS3	Not assessed	Not assessed: no NMD-inhibited RNA result, proficient protein/mRNA assay, or benign-range calibrated functional odds are available for PMS2 c.353+7C>A.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	Not assessed: no non-segregation pedigree data or combined Bayes likelihood ratio is provided for comparison with the VCEP thresholds of <0.05 or >0.05 to 0.48.	cspec
BP1	N/A	Not applicable: BP1 is explicitly excluded by the PMS2 VCEP specification, and this variant has an unknown protein consequence.	cspec
BP2	N/A	Not applicable: the PMS2 VCEP marks BP2 not applicable and directs use of BS2 instead.	cspec
BP3	N/A	Not applicable: the PMS2 VCEP explicitly marks BP3 Not Applicable, and this is an intronic SNV rather than an in-frame repeat-region indel.	cspec
BP4	Met	Met, Supporting: SpliceAI maximum delta score 0.014 satisfies the VCEP intronic BP4 threshold of <=0.1.	cspec spliceai vcep_hci_priors_pms2
BP5	Not assessed	Not assessed: COSMIC reports 2 somatic observations, but no qualifying tumor MSS/IHC or BRAF/MLH1-methylation evidence is available for BP5.	cspec cosmic
BP6	N/A	Not applicable: the PMS2 VCEP prohibits BP6, regardless of the exact variant's likely-benign ClinVar reports.	cspec clinvar
BP7	Met	Met, Supporting: c.353+7 is an intronic position at the VCEP's included +7 boundary for BP7.	cspec

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