Variant classification summary

NM_000535.7:c.706-13T>C

PMS2 · NP_000526.2:p.? · NM_000535.7

GRCh37: chr7:6037067 A>G · GRCh38: chr7:5997436 A>G

Gene: PMS2 Transcript: NM_000535.7

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.?

gnomAD AF

9.965890080218772e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 Supporting: gnomAD v4.1 allele frequency 9.96589e-06 is below the VCEP threshold of 0.00002.

2

BP4 Supporting: SpliceAI maximum delta score 0.009 is within the VCEP no-splicing-impact threshold of <=0.1.

Final determination: Under the PMS2 VCEP Version 2.0 framework, PM2 Supporting plus BP4 Supporting satisfies no pathogenic or benign rule, so the call is VUS.

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	Not assessed	Not assessed: this non-canonical intronic variant has SpliceAI maximum delta 0.009 and lacks RNA evidence establishing a qualifying loss-of-function consequence.	cspec spliceai pvs1_variant_assessment vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PS1	Not assessed	Not assessed: no qualifying VCEP Pathogenic or Likely Pathogenic comparator was available for this non-canonical splice nucleotide.	cspec spliceai clinvar
PS2	Not assessed	Not assessed: no documented de novo observation, parental testing, confirmed parentage, or VCEP de novo-point assignment is available.
PS3	Not assessed	Not assessed: no variant-specific functional assay result, functional odds, or RNA assay outcome is available for PMS2 c.706-13T>C.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PS4	N/A	Not applicable: the PMS2 VCEP excludes PS4 proband-counting evidence because tumor IHC data are evaluated under PP4.	cspec
PM1	N/A	Not applicable: the PMS2 VCEP explicitly marks PM1 Not Applicable despite functional-domain information.	cspec vcep_mmr_functional_domains
PM2	Met	Met at Supporting: gnomAD v4.1 allele frequency is 9.96589e-06, below the VCEP PM2 threshold of 0.00002.	gnomad_v4 vcep_vcep_pilot_variants_mmr cspec
PM3	Not assessed	Not assessed: no affected proband, qualifying pathogenic PMS2 allele in trans, confirmed phase, or PM3 point total is documented.	cspec
PM4	N/A	Not applicable: the PMS2 VCEP explicitly designates PM4 as Not Applicable, regardless of this variant's intronic p.? consequence.	cspec pvs1_variant_assessment vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PM5	N/A	Not applicable: c.706-13T>C is intronic with protein consequence p.?, not a missense change at an amino-acid residue.	cspec pm5_candidates
PM6	N/A	Not applicable: the ClinGen InSiGHT PMS2 VCEP specification explicitly marks PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no pedigree observations, informative meioses, or combined Bayes Likelihood Ratio are available for segregation analysis.
PP2	N/A	Not applicable: the PMS2 VCEP explicitly excludes PP2, and this variant is intronic rather than missense.	cspec
PP3	Not met	Not met: SpliceAI maximum delta score 0.009 is below the VCEP PP3 splice-defect threshold of 0.2.	cspec spliceai vcep_hci_priors_pms2
PP4	Not assessed	Not assessed: no qualifying MSI-H tumor count or PMS2-consistent protein-loss result is available to compare with the VCEP PP4 rule.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
PP5	N/A	Not applicable: the PMS2 VCEP prohibits PP5, regardless of the ClinVar classifications reported for this variant.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 Grpmax filtering allele frequency is 7.49e-06, below the VCEP BA1 threshold of 0.0028.	gnomad_v4 vcep_vcep_pilot_variants_mmr cspec
BS1	Not met	Not met: gnomAD v4.1 Grpmax filtering allele frequency is 7.49e-06, below the VCEP BS1 lower threshold of 0.00028.	gnomad_v4 vcep_vcep_pilot_variants_mmr cspec
BS2	Not assessed	Not assessed: no documented in-trans co-occurrence, confirmed phase, qualifying cancer age, or absence of CMMRD manifestations is available.	cspec
BS3	Not assessed	Not assessed: no variant-specific proficient-function result, functional odds, or NMD-inhibited RNA assay outcome is available for PMS2 c.706-13T>C.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	Not assessed: no unaffected carrier observations, non-segregation data, informative meioses, or combined Bayes Likelihood Ratio are available.
BP1	N/A	Not applicable: the PMS2 VCEP explicitly excludes BP1, and this variant is intronic rather than missense.	cspec
BP2	N/A	Not applicable: the PMS2 VCEP explicitly designates BP2 as Not Applicable.	cspec
BP3	N/A	Not applicable: the PMS2 VCEP explicitly designates BP3 as Not Applicable, so repeat-region context cannot support this criterion.	cspec pvs1_variant_assessment vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
BP4	Met	Met at Supporting: SpliceAI maximum delta score 0.009 is within the VCEP BP4 no-impact threshold of <=0.1.	cspec spliceai vcep_hci_priors_pms2
BP5	Not assessed	Not assessed: no patient-specific MSS, MMR-protein, BRAF V600E, or MLH1-methylation tumor result is available for the BP5 rule.	cspec
BP6	N/A	Not applicable: the PMS2 VCEP prohibits BP6, regardless of the ClinVar benign or likely benign submissions.	cspec clinvar
BP7	N/A	Not applicable: c.706-13T>C is 13 bases upstream of the exon, outside BP7's intronic at-or-beyond -21/+7 scope.	cspec

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