Variant classification summary

NM_000535.7:c.137G>T

PMS2 · NP_000526.2:p.(Ser46Ile) · NM_000535.7

GRCh37: chr7:6045549 C>A · GRCh38: chr7:6005918 C>A

Gene: PMS2 Transcript: NM_000535.7

Final call

VUS

PP3 moderate PP4 supporting PP5 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Ser46Ile)

gnomAD AF

0.00028185277848482405 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PP3 Moderate: HCI MAPP/PP2 Prior P is 0.9387, above the VCEP threshold of >0.81.

2

PP4 Supporting: variant-specific colorectal-cancer evidence shows tumor PMS2 loss.

3

PP5 Supporting: an InSiGHT expert panel classification reported the variant as Likely pathogenic.

Final determination: Under the PMS2 VCEP Version 2.0 framework, PP3 at Moderate plus PP4 and PP5 at Supporting does not satisfy any Pathogenic, Likely Pathogenic, Benign, or Likely Benign rule, so the result 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	N/A	Not applicable: c.137G>T is a missense variant, whereas the PMS2 VCEP PVS1 rule names nonsense, frameshift, genomic, initiation-codon, and qualifying splice consequences.	cspec vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PS1	Not assessed	Not assessed: no different-nucleotide p.Ser46Ile variant classified Pathogenic by this VCEP was identified.
PS2	Not met	Not met: constitutional testing supports paternal inheritance of p.Ser46Ile, not a de novo origin in the proband.	cspec PMID:16144131
PS3	Not assessed	Not assessed: one assay showed 12.75% ± 4.68% repair versus wild type, but VCEP flowchart confirmation requires two independent concordant assays or calibrated functional odds.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:23709753
PS4	N/A	Not applicable: the PMS2 VCEP explicitly does not use PS4 because tumor IHC evidence is evaluated through PP4.	cspec
PM1	N/A	Not applicable: the PMS2 VCEP marks PM1 Not applicable, despite residue 46 lying within its ATPase domain at residues 1-365.	cspec vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 Grpmax FAF is 0.00032437, exceeding the VCEP PM2 rarity threshold of 0.00002.	cspec gnomad_v4
PM3	Not assessed	Not assessed: two biallelic observations are reported, but the VCEP text does not provide point weights needed to calculate the required PM3 total.	cspec PMID:16144131 PMID:18602922
PM4	N/A	Not applicable: the PMS2 VCEP explicitly designates PM4 as Not Applicable for this framework.	cspec
PM5	Not assessed	Not assessed: residue-46 alternatives were listed, but no different missense change was classified Pathogenic or Likely Pathogenic by this VCEP.	vcep_hci_priors_pms2 pm5_candidates
PM6	N/A	Not applicable: the PMS2 VCEP explicitly marks PM6 as Not Applicable.	cspec
PP1	Not assessed	Not assessed: no combined co-segregation Bayes Likelihood Ratio is reported for comparison with the VCEP thresholds.	cspec PMID:16144131
PP2	N/A	Not applicable: the PMS2 VCEP explicitly marks PP2 Not applicable for this gene framework.	cspec
PP3	Met	Met at Moderate: HCI MAPP/PP2 Prior P is 0.9387, exceeding the VCEP PP3_Moderate threshold of >0.81.	cspec vcep_hci_priors_pms2
PP4	Met	Met, Supporting: variant-specific colorectal-cancer evidence includes a PMS2-negative tumor, satisfying the VCEP requirement for one qualifying tumor.	cspec PMID:23709753 PMID:16144131
PP5	Met	Not applicable: the PMS2 VCEP explicitly excludes PP5 from use for this framework.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 Grpmax FAF is 0.00032437, below the VCEP BA1 threshold of 0.0028 (0.28%).	cspec gnomad_v4
BS1	Not assessed	Not assessed: Grpmax FAF 0.00032437 fits BS1, but the required exclusion of a founder pathogenic variant is unresolved.	cspec gnomad_v4 PMID:18602922
BS2	Not assessed	Not assessed: reported PMS2 co-occurrences do not establish the VCEP-required phase, qualifying cancer age, and absence of CMMRD conditions.	cspec PMID:16144131 PMID:18602922
BS3	Not assessed	Not assessed: no proficient-function result or calibrated odds are available, and the single reported assay showed reduced rather than normal MMR activity.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:23709753
BS4	Not assessed	Not assessed: no combined non-segregation Bayes Likelihood Ratio is available for comparison with the VCEP BS4 intervals.	cspec
BP1	N/A	Not applicable: the PMS2 VCEP explicitly marks BP1 Not applicable for missense variants in this framework.	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, regardless of repeat-region context.	cspec
BP4	Not met	Not met: HCI MAPP/PP2 Prior P is 0.9387, not below the VCEP BP4 threshold of <0.11.	cspec vcep_hci_priors_pms2
BP5	Not assessed	Not assessed: available tumor evidence shows PMS2 loss, but no VCEP-qualifying MSS, intact-expression, BRAF V600E, or MLH1-methylation evidence is documented.	cspec PMID:23709753 PMID:16144131
BP6	N/A	Not applicable: the PMS2 VCEP explicitly excludes BP6 from use for this framework.	cspec
BP7	N/A	Not applicable: c.137G>T is missense, whereas the VCEP BP7 rule covers only synonymous or intronic variants.	cspec

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