Variant classification summary

NM_000535.7:c.73C>T

PMS2 · NP_000526.2:p.(Gln25Ter) · NM_000535.7

GRCh37: chr7:6045613 G>A · GRCh38: chr7:6005982 G>A

Gene: PMS2 Transcript: NM_000535.7

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Gln25Ter)

gnomAD AF

6.208187854797936e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PVS1 very strong applies because the nonsense variant truncates PMS2 at codon 25, within the VCEP threshold of codon 798 or earlier.

2

VUS: PM2 supporting applies because the gnomAD v4.1 allele frequency is 6.20819e-07, below 0.00002.

Final determination: Under the PMS2 VCEP Version 2.0 criteria-combination rules, PVS1 very strong with only PM2 supporting does not satisfy a pathogenic or benign rule, so the final 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	Met	Met, very strong: the PMS2 nonsense variant creates a premature stop at codon 25, within the VCEP threshold of codon 798 or earlier.	cspec pvs1_variant_assessment vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PS1	N/A	Not applicable: the VCEP limits PS1 to predicted missense or specified non-canonical splice variants, whereas NM_000535.7:c.73C>T is a nonsense change, p.(Gln25Ter).	cspec
PS2	Not assessed	Not assessed: no proband-specific de novo finding, parental testing, or VCEP de novo point total is available for this variant.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay result is available to compare with the VCEP's calibrated assay criteria or functional-assay flowchart.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PS4	N/A	Not applicable: the PMS2 VCEP does not use PS4 proband counting because tumor IHC data are available for PP4 classification.	cspec
PM1	N/A	Not applicable: the PMS2 VCEP explicitly marks PM1 Not Applicable, and its domain-table material contains no authoritative PMS2 domain entry for residue 25.	cspec vcep_mmr_functional_domains
PM2	Met	Met at Supporting: gnomAD v4 total AF 6.20819e-07 is below 0.00002, with 1 allele in 1,610,776 and no homozygotes.	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr
PM3	Not assessed	Not assessed: no affected-proband observation, pathogenic PMS2 allele, or confirmed trans/cis phase is documented to generate a PM3 point total.	cspec PMID:16144131
PM4	N/A	Not applicable: the PMS2 Version 2.0 VCEP specification explicitly designates PM4 as not applicable.	cspec
PM5	N/A	Not applicable: the VCEP restricts PM5 to missense changes at the same residue, whereas p.(Gln25Ter) is a nonsense variant.	cspec
PM6	N/A	Not applicable: the PMS2 VCEP explicitly marks PM6 as Not Applicable for this framework.	cspec
PP1	Not assessed	Not assessed: no variant-specific pedigree, relative genotypes, meioses, or combined Bayes Likelihood Ratio is available for PP1.	cspec
PP2	N/A	Not applicable: the PMS2 VCEP explicitly marks PP2 Not Applicable.	cspec
PP3	N/A	Not applicable: PP3 covers missense or non-canonical splice variants, whereas c.73C>T is a nonsense variant producing p.Gln25Ter.	cspec
PP4	Not assessed	Not assessed: no patient-specific MSI, tumor-genome, or PMS2 IHC result is available to compare with the VCEP PP4 tumor-evidence rule.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
PP5	N/A	Not applicable: the PMS2 VCEP explicitly prohibits use of PP5, regardless of ClinVar pathogenic reports.	cspec clinvar
BA1	Not assessed	Not assessed: gnomAD v4 total AF is 6.20819e-07, but the VCEP requires a Grpmax filtering AF, which is unavailable.	cspec gnomad_v4
BS1	Not assessed	Not assessed: gnomAD v4 total AF is 6.20819e-07, but the VCEP requires a Grpmax filtering AF, which is unavailable.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying in-trans co-occurrence, cancer-age, CMMRD-exclusion, or phase-confirmation evidence is available.	cspec
BS3	Not assessed	Not assessed: no variant-specific proficient-function result or calibrated functional odds are available for comparison with the VCEP BS3 thresholds.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	Not assessed: no variant-specific non-segregation pedigree, relative data, meioses, or combined Bayes Likelihood Ratio is available for BS4.	cspec
BP1	N/A	Not applicable: the PMS2 VCEP explicitly marks BP1 Not Applicable.	cspec
BP2	N/A	Not applicable: the PMS2 VCEP specification explicitly designates BP2 as Not Applicable.	cspec
BP3	N/A	Not applicable: the PMS2 Version 2.0 VCEP specification explicitly designates BP3 as not applicable.	cspec
BP4	N/A	Not applicable: BP4 covers missense, intronic, or synonymous variants, whereas c.73C>T is a nonsense variant producing p.Gln25Ter.	cspec
BP5	Not assessed	Not assessed: no patient-specific MSS, MMR-protein, BRAF V600E, or MLH1-methylation tumor evidence is available for the BP5 alternate-basis rule.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
BP6	N/A	Not applicable: the PMS2 VCEP explicitly prohibits use of BP6 for this gene-specific interpretation.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous or intronic variants, whereas c.73C>T is a nonsense variant producing p.Gln25Ter.	cspec

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