Variant classification summary

NM_000535.7:c.14A>T

PMS2 · NP_000526.2:p.(Glu5Val) · NM_000535.7

GRCh37: chr7:6048637 T>A · GRCh38: chr7:6009006 T>A

Gene: PMS2 Transcript: NM_000535.7

Final call

PM2 supporting BP4 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Glu5Val)

gnomAD AF

4.961351075124778e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000535.7:c.14A>T (p.Glu5Val) is a missense variant in exon 1 of PMS2. It is extremely rare in population databases (gnomAD v4.1: 8/1,612,464 alleles, AF=4.96e-06), meeting PM2_Supporting per InSiGHT/ClinGen PMS2 VCEP v2.0.0.

2

Multiple in silico predictors support a benign effect: the HCI prior probability for pathogenicity is 0.004 (meeting BP4_Supporting), REVEL score is 0.498, BayesDel score is 0.008, and SpliceAI predicts no splicing impact (max delta = 0.00).

3

No functional data, segregation data, de novo observations, or tumor phenotype data (MSI/IHC) are available for this variant. ClinVar reports this variant as Uncertain Significance (VCV231310, 7 submitters, criteria provided single submitter).

4

The variant does not meet criteria for PVS1 (missense, not a null variant), PS1 (no same-amino-acid pathogenic comparator), PS3 (no functional data), PM5 (no same-residue pathogenic comparator), or any other pathogenic criterion.

5

The only criteria met are PM2_Supporting (extremely rare in gnomAD) and BP4_Supporting (benign in silico predictions including HCI prior <0.11). With one pathogenic supporting and one benign supporting criterion, the evidence is insufficient to reach a Likely Pathogenic or Likely Benign classification under the VCEP combining rules. The variant remains a Variant of Uncertain Significance.

Final determination: Rule31 in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 2.0.0 v2.0.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Uncertain Significance - Conflicting Evidence.

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	PVS1 is not applicable: NM_000535.7:c.14A>T is a missense variant (p.Glu5Val), not a nonsense, frameshift, canonical splice (±1,2), initiation codon, or large genomic alteration. The VCEP PVS1 rules for PMS2 apply only to null variant classes.
PS1	Not met	PS1 is not met: no different nucleotide change at Glu5 encoding the same Val substitution has been previously classified as Pathogenic by the InSiGHT/ClinGen VCEP for PMS2.
PS2	Not assessed	PS2 is not assessed: no de novo observation data for this variant were identified in ClinVar submissions, literature, or any supporting databases.
PS3	Not met	PS3 is not met: no variant-specific functional assay data are available for NM_000535.7:c.14A>T (p.Glu5Val). OncoKB reports Unknown Oncogenic Effect with no variant-specific PMIDs. No calibrated functional odds data exist for this variant in the MMR functional assay SVI documentation.
PS4	N/A	PS4 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification.
PS5	N/A	PS5 is not applicable: not defined in the InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification, and PP5 is explicitly listed as Not Applicable by this VCEP.
PM1	N/A	PM1 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification.
PM2	Met	PM2_Supporting is met: NM_000535.7:c.14A>T is extremely rare in gnomAD v4.1 (AF=4.96e-06, 8/1,612,464 alleles, grpmax FAF=2.92e-06), which falls below the VCEP threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0.	gnomad_v4
PM5	Not met	PM5 is not met: no different missense variant at PMS2 residue Glu5 has been classified as Pathogenic or Likely Pathogenic by the VCEP. The PM5 candidate search identified zero same-residue comparators meeting the VCEP threshold.
PM6	N/A	PM6 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification.
PP1	Not met	PP1 is not met: no co-segregation data (Bayes Likelihood Ratio) are available for NM_000535.7:c.14A>T in any pedigree. The single full-text publication reviewed (PMID:25070057) is a general Lynch syndrome management guideline and contains no variant-specific segregation analysis.
PP2	N/A	PP2 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification.
PP3	Not met	PP3 is not met: the HCI prior probability for pathogenicity is 0.004, which is far below both the VCEP Moderate threshold (>0.81) and the Supporting threshold (>0.68 and ≤0.81). SpliceAI predicts no splicing impact (max delta score = 0.00, below the 0.2 threshold). REVEL score is 0.498 and BayesDel is 0.008, consistent with a benign in silico profile.	hci_prior spliceai revel bayesdel
PP4	Not assessed	PP4 is not assessed: no tumor MSI/IHC data (MSI-H status, MMR protein expression) are available for patients carrying NM_000535.7:c.14A>T. The VCEP requires tumor phenotype data (CRC/endometrial MSI-H and/or loss of MMR protein expression consistent with PMS2) to apply this criterion.
PP5	N/A	PP5 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification.
BA1	Not met	BA1 is not met: the gnomAD v4.1 grpmax filtering allele frequency is 2.92e-06, far below the VCEP stand-alone benign threshold of ≥0.0028 (0.28%).	gnomad_v4
BS1	Not met	BS1 is not met: the gnomAD v4.1 grpmax filtering allele frequency is 2.92e-06, far below the VCEP strong benign threshold of ≥0.00028 (0.028%).	gnomad_v4
BS2	Not met	BS2 is not met: no evidence of this variant occurring in trans with a known pathogenic PMS2 variant in a CRC patient over age 45 without CMMRD features.
BS3	Not met	BS3 is not met: no calibrated functional assay data are available for NM_000535.7:c.14A>T. No evidence of proficient MMR function or normal splicing has been demonstrated for this specific variant in laboratory assays.
BS4	Not met	BS4 is not met: no co-segregation data (lack of segregation with disease) are available for this variant. The single full-text publication reviewed (PMID:25070057) is a general guideline and contains no variant-specific segregation analysis.
BP1	N/A	BP1 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification.
BP2	N/A	BP2 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification.
BP4	Met	BP4_Supporting is met: the HCI prior probability for pathogenicity is 0.004, which falls below the VCEP threshold of <0.11 for BP4_Supporting. Multiple in silico predictors support a benign effect: REVEL score 0.498 (below typical pathogenic threshold), BayesDel score 0.008 (strongly benign), and SpliceAI delta 0.00 (no splicing impact).	hci_prior revel bayesdel spliceai
BP5	Not met	BP5 is not met: no tumor data demonstrating MSS status, intact MMR protein expression, or BRAF V600E/MLH1 methylation in carriers of this variant are available.
BP6	N/A	BP6 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification.
BP7	Not met	BP7 is not met: this criterion applies only to synonymous (silent) or intronic variants at or beyond positions -21/+7. NM_000535.7:c.14A>T is a missense variant (p.Glu5Val) and does not qualify.

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