Variant classification summary

NM_000535.7:c.1145-11C>T

PMS2 · NP_000526.2:p.? · NM_000535.7

GRCh37: chr7:6027262 G>A · GRCh38: chr7:5987631 G>A

Gene: PMS2 Transcript: NM_000535.7

Final call

Likely Benign

PP3 supporting BS1 strong BP7 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.?

gnomAD AF

6.351071855642062e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: PP3 (supporting) is met because SpliceAI max delta 0.213 meets the PMS2 non-canonical splice threshold.

2

Likely Benign: BS1 (strong) is met because gnomAD v4.1 Grpmax FAF 0.00072958 falls within the PMS2 BS1 interval.

3

Likely Benign: BP7 (supporting) is met because the intronic position -11 lies within the PMS2 VCEP BP7 range.

Final determination: Under Rule18 of the ClinGen InSiGHT PMS2 Version 2.0 framework, one Benign Strong criterion plus one Benign Supporting criterion yields Likely Benign.

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 met	Not met: NM_000535.7:c.1145-11C>T is an intronic −11 variant outside the PMS2 VCEP’s ±1/2 splice-site PVS1 rule.	cspec spliceai
PS1	Not assessed	Not assessed: SpliceAI max delta is 0.213, but no qualifying pathogenic comparator at the same non-canonical splice nucleotide is documented.	cspec spliceai
PS2	Not assessed	Not assessed: no proband-level de novo observation, parental confirmation, tumor consistency, or de novo point total is documented.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional or RNA assay is reported; SpliceAI max delta 0.213 is predictive, not functional evidence.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart spliceai
PS4	N/A	Not applicable: the PMS2 VCEP explicitly excludes PS4 because tumor IHC evidence is evaluated through PP4 instead.	cspec
PM1	N/A	Not applicable: the PMS2 VCEP explicitly marks PM1 as not applicable, and no approved PMS2 domain-table entry is supplied.	cspec
PM2	Not met	Not met: gnomAD v4.1 total AF was 0.0000635107, exceeding the VCEP PM2 threshold of less than 0.00002.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected-proband CMMRD observation or pathogenic PMS2 partner with documented phase is available to assign the VCEP's PM3 points.	cspec
PM4	N/A	Not applicable: the PMS2 VCEP explicitly excludes PM4, and this intronic variant has no established in-frame protein length change.	cspec
PM5	N/A	Not applicable: this is an intronic variant with protein consequence p.? rather than a missense change eligible for same-residue PM5.	cspec pm5_candidates
PM6	N/A	Not applicable: the PMS2 VCEP incorporates assumed de novo evidence into PS2 at 0.5 points rather than using PM6.	cspec
PP1	Not assessed	Not assessed: no informative pedigree, meioses, affected-relative testing, or combined Bayes Likelihood Ratio is documented.	cspec
PP2	N/A	Not applicable: the PMS2 VCEP explicitly marks PP2 as not applicable, and this variant is intronic rather than missense.	cspec
PP3	Met	Met at Supporting: SpliceAI max delta 0.213 meets the PMS2 VCEP non-canonical splice threshold of >=0.2.	cspec spliceai vcep_hci_priors_pms2
PP4	Not assessed	Not assessed: no patient-specific MSI, tumor-genome, or PMS2 IHC result is available to satisfy the PP4 tumor-evidence rule.	cspec
PP5	N/A	Not applicable: the PMS2 VCEP excludes PP5, and ClinVar reports zero exact-variant expert-panel submissions.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 Grpmax FAF was 0.00072958, below the VCEP BA1 threshold of 0.0028.	cspec gnomad_v4
BS1	Met	Met at Strong: gnomAD v4.1 Grpmax FAF was 0.00072958, within the VCEP BS1 interval of 0.00028 to below 0.0028.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no documented in-trans pathogenic PMS2 variant, phase confirmation, qualifying age, or CMMRD assessment is available for the BS2 rule.	cspec
BS3	Not assessed	Not assessed: no variant-specific benign functional or RNA result is reported; SpliceAI max delta 0.213 cannot establish proficient function.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart spliceai
BS4	Not assessed	Not assessed: no documented non-segregating affected relatives, informative meioses, or combined Bayes Likelihood Ratio is available.	cspec
BP1	N/A	Not applicable: the PMS2 VCEP explicitly marks BP1 as not applicable, and this variant is intronic rather than missense.	cspec
BP2	N/A	Not applicable: the PMS2 VCEP explicitly designates BP2 as not applicable for this gene-specific framework.	cspec
BP3	N/A	Not applicable: the PMS2 VCEP excludes BP3, and this is an intronic variant rather than an in-frame repeat-region insertion or deletion.	cspec
BP4	Not met	Not met: SpliceAI max delta 0.213 exceeds the PMS2 VCEP no-impact threshold of <=0.1.	cspec spliceai vcep_hci_priors_pms2
BP5	Not assessed	Not assessed: no tumor MSS/IHC, BRAF V600E, or MLH1 methylation findings are available for the BP5 alternate-basis rule.	cspec
BP6	N/A	Not applicable: the PMS2 VCEP excludes BP6, and ClinVar reports zero exact-variant expert-panel submissions.	cspec clinvar
BP7	Met	Met at Supporting: c.1145-11C>T is intronic at -11, within the PMS2 VCEP BP7 range of -21/+7.	cspec

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