Variant classification summary

NM_000535.7:c.1268C>G

PMS2 · NP_000526.2:p.(Ala423Gly) · NM_000535.7

GRCh37: chr7:6027128 G>C · GRCh38: chr7:5987497 G>C

Gene: PMS2 Transcript: NM_000535.7

Final call

VUS

BP4 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Ala423Gly)

gnomAD AF

3.96522497695213e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 supporting: the HCI MAPP/PP2 Prior P score is 0.088, below the PMS2 VCEP cutoff of <0.11.

Final determination: Because only BP4 supporting is applied and no VCEP pathogenic or benign rule is met, the PMS2 VCEP criteria-combination framework assigns 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.1268C>G is a missense SNV yielding p.Ala423Gly, outside the PMS2 VCEP's named nonsense, frameshift, splice, and genomic-alteration PVS1 classes.	cspec vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PS1	Not assessed	Not assessed: no VCEP-established Pathogenic PMS2 variant with a different nucleotide change encoding p.Ala423Gly was identified.	cspec
PS2	Not assessed	Not assessed: no proband-parent testing or de novo point assignment is documented for NM_000535.7:c.1268C>G.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional readout, calibrated functional odds, or concordant assay result is available for PMS2 p.Ala423Gly.	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 evidence is handled through PP4.	cspec
PM1	N/A	Not applicable: the PMS2 VCEP explicitly designates PM1 Not Applicable, and residue 423 is outside the listed PMS2 domains.	cspec vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 allele frequency is 0.0000396522 (64/1,614,032), exceeding the VCEP PM2 threshold of <0.00002.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation, pathogenic allele in trans, phase determination, or PM3 point assignment is available for this variant.
PM4	N/A	Not applicable: the PMS2 VCEP marks PM4 Not Applicable, and c.1268C>G is a missense SNV with no protein-length change.	cspec
PM5	Not assessed	Not assessed: no same-residue missense comparator with a qualifying VCEP Pathogenic or Likely Pathogenic classification was identified.	cspec
PM6	N/A	Not applicable: the PMS2 VCEP specification explicitly marks PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no informative pedigree or combined Bayes Likelihood Ratio is documented for co-segregation with disease.	cspec
PP2	N/A	Not applicable: the PMS2 VCEP explicitly designates PP2 Not Applicable.	cspec
PP3	Not met	Not met: HCI MAPP/PP2 Prior P score is 0.088, below the PP3 Supporting threshold of >0.68 for this missense variant.	cspec vcep_hci_priors_pms2
PP4	Not assessed	Not assessed: no case-specific MSI-H tumor or PMS2-consistent loss-of-expression evidence is available to meet the PP4 threshold.	cspec
PP5	N/A	Not applicable: the PMS2 VCEP explicitly excludes PP5 from use for variant classification.	cspec
BA1	Not met	Not met: gnomAD v4.1 Grpmax FAF is 0.00004101 (0.004101%), below the VCEP BA1 threshold of 0.0028 (0.28%).	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 Grpmax FAF is 0.00004101, below the VCEP BS1 lower threshold of 0.00028 (0.028%).	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying in-trans co-occurrence, phase confirmation, cancer-age, or CMMRD-exclusion evidence is available for the BS2 rule.	cspec
BS3	Not assessed	Not assessed: no variant-specific proficient-function result, calibrated functional odds, or qualifying protein/mRNA assay result is available for PMS2 p.Ala423Gly.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	Not assessed: no informative non-segregating relatives or combined Bayes Likelihood Ratio is documented.	cspec
BP1	N/A	Not applicable: the PMS2 VCEP explicitly designates BP1 Not Applicable.	cspec
BP2	N/A	Not applicable: the PMS2 VCEP marks BP2 not applicable and directs use of BS2 instead.	cspec
BP3	N/A	Not applicable: the PMS2 VCEP marks BP3 Not Applicable, and c.1268C>G is a missense SNV rather than a repeat-region in-frame indel.	cspec
BP4	Met	Met at Supporting: HCI MAPP/PP2 Prior P score is 0.088, below the VCEP BP4 cutoff of <0.11.	cspec vcep_hci_priors_pms2
BP5	Not assessed	Not assessed: no qualifying MSS, inconsistent MMR-expression, BRAF V600E, or MLH1-methylation tumor evidence is available.	cspec
BP6	N/A	Not applicable: the PMS2 VCEP explicitly excludes BP6 from use for variant classification.	cspec
BP7	N/A	Not applicable: c.1268C>G is a missense variant, whereas BP7 covers only synonymous or intronic variants.	cspec

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