Variant classification summary

NM_000535.7:c.1501G>A

PMS2 · NP_000526.2:p.(Val501Met) · NM_000535.7

GRCh37: chr7:6026895 C>T · GRCh38: chr7:5987264 C>T

Gene: PMS2 Transcript: NM_000535.7

Final call

VUS

BP4 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Val501Met)

gnomAD AF

5.6378237256969525e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 Supporting: the PMS2 HCI prior pathogenicity probability is 0.002, below the VCEP BP4 threshold of <0.11.

Final determination: No PMS2 VCEP Version 2.0 criteria-combination rule matched the adjudicated evidence, so the variant remains a Variant of Uncertain Significance.

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: PMS2 c.1501G>A is a missense variant producing p.(Val501Met), not a VCEP-defined loss-of-function or qualifying splice consequence.	cspec vcep_pvs1_decisiontree_mmr pvs1_variant_assessment
PS1	Not met	Not met: no alternate-nucleotide PMS2 variant encoding p.Val501Met is established by the VCEP as Pathogenic.	cspec
PS2	Not assessed	Not assessed: no proband-specific de novo observation, parental confirmation, LS-spectrum tumor evidence, or de novo point total is documented.	cspec
PS3	Not assessed	Not assessed: no variant-specific PMS2 functional assay result or calibrated functional odds are available to meet the VCEP PS3 thresholds of >2.08, >4.3, or >18.7.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:26467025 PMID:28492532
PS4	N/A	Not applicable: the PMS2 VCEP explicitly excludes PS4 proband counting because tumor IHC evidence is evaluated through PP4.	cspec
PM1	N/A	Not applicable: the governing PMS2 VCEP explicitly designates PM1 as Not Applicable.	cspec vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 allele frequency is 5.6378237256969525e-05, exceeding the PMS2 PM2 threshold of 0.00002.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation documents a second pathogenic PMS2 variant in trans or provides phase evidence needed for PM3 points.	cspec
PM4	N/A	Not applicable: the PMS2 VCEP excludes PM4, and c.1501G>A is a missense substitution with no protein-length change.	cspec pvs1_variant_assessment
PM5	Not met	Not met: zero same-residue Val501 comparator candidates were found, and the HCI prior probability is 0.002 versus the >0.68 PP3-supporting threshold.	cspec pm5_candidates hci_prior
PM6	N/A	Not applicable: the governing PMS2 VCEP explicitly designates PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no tested relatives, pedigree segregation data, meioses, or combined Bayes likelihood ratio is documented.	cspec
PP2	N/A	Not applicable: the governing PMS2 VCEP explicitly designates PP2 as Not Applicable.	cspec
PP3	Not met	Not met: HCI prior pathogenicity probability 0.002 is below the PMS2 VCEP PP3 supporting threshold of >0.68.	vcep_hci_priors_pms2 hci_prior revel cspec
PP4	Not assessed	Not assessed: no variant-specific MSI, tumor-genome, or PMS2-consistent IHC result is available to compare with the VCEP's one-tumor PP4 threshold.	cspec
PP5	N/A	Not applicable: the PMS2 VCEP excludes PP5, and ClinVar has zero exact-variant expert-panel Pathogenic or Likely pathogenic submissions.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax filtering allele frequency is 5.628e-05, below the PMS2 BA1 threshold of 0.0028.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax filtering allele frequency is 5.628e-05, below the PMS2 BS1 lower threshold of 0.00028.	cspec gnomad_v4
BS2	Not assessed	Not assessed: gnomAD v4.1 shows zero homozygotes, but the PMS2 BS2 rule requires documented in-trans clinical co-occurrence and confirmed phase.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific proficient assay result or calibrated functional odds are available to meet the VCEP BS3 thresholds of <=0.05 or >0.05 and <=0.48.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:26467025 PMID:28492532
BS4	Not assessed	Not assessed: no non-segregating affected relatives, pedigree analysis, or combined Bayes likelihood ratio is documented.	cspec
BP1	N/A	Not applicable: the governing PMS2 VCEP explicitly designates BP1 as Not Applicable.	cspec
BP2	N/A	Not applicable: the PMS2 VCEP explicitly excludes BP2 and directs evaluators to use BS2 instead.	cspec
BP3	N/A	Not applicable: the PMS2 VCEP excludes BP3, and c.1501G>A is a missense substitution rather than a repeat-region in-frame deletion.	cspec pvs1_variant_assessment
BP4	Met	Met, Supporting: HCI prior pathogenicity probability 0.002 is below the PMS2 VCEP BP4 threshold of <0.11.	vcep_hci_priors_pms2 hci_prior revel cspec
BP5	Not assessed	Not assessed: no qualifying tumor phenotype, BRAF V600E, or MLH1 methylation result is available for comparison with the BP5 tumor-count thresholds.	cspec
BP6	N/A	Not applicable: the PMS2 VCEP excludes BP6, and ClinVar has zero exact-variant expert-panel Benign or Likely benign submissions.	cspec clinvar
BP7	N/A	Not applicable: c.1501G>A is a missense variant, whereas BP7 applies only to qualifying synonymous or intronic variants.	cspec

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