PM2_Supporting is met: the variant is absent from gnomAD v4.1, meeting the VCEP threshold of <0.00002 allele frequency.1 PP3_Moderate is met: the HCI MAPP/PP2 Prior probability for p.Asp699Val is 0.8907, exceeding the VCEP PP3_Moderate threshold of >0.81.2 Multiple criteria could not be assessed due to absence of variant-specific data: PS3 (functional assays), PP1 (co-segregation), PP4 (tumor phenotype), BS2 (co-occurrence in trans), BS3 (benign functional evidence), BS4 (lack of co-segregation), and BP5 (tumor MSS/IHC data). The variant has not been observed in population databases and is predicted damaging by multiple in silico tools (REVEL 0.969, BayesDel 0.419), but no clinical case reports, tumor data, or functional studies have been identified to further support or refute pathogenicity.3
PMS2
Final classification
VUS
PMS2 c.2096A>T · p.Asp699Val
PMS2
PM2_Supporting is met: the variant is absent from gnomAD v4.1, meeting the VCEP threshold of <0.00002 allele frequency.
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 was evaluated deterministically with applied criteria: PM2 supporting, PP3 moderate; no rule matched the adjudicated criteria.
Classification rationale
PM2PP3
VUS
PMS2 c.2096A>T
PM2 + PP3
→
VUS
2
hci_priorvcep_hci_priors_pms2cspec ↗
3
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗revelbayesdel
Gene diagram
· NM_000535.7 · variants mapped to exon structure
PMS2
NM_000535.7
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
The variant is absent from gnomAD v4.1, meeting the VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles).
Absent from gnomAD v4.1 (AF = 0)Absent from gnomAD v2.1Absent from gnomAD-Canada v1.0
✓
PP3
moderate
Pathogenic
HCI MAPP/PP2 Prior probability for c.2096A>T (p.D699V) is 0.8907, which exceeds the VCEP PP3_Moderate threshold of >0.81.
HCI prior probability = 0.8907MAPP score = 22.25Custom PP2 score = 0.999
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at codon 699 producing p.(Asp699Val) has been established as Pathogenic by this VCEP.
PS2
No de novo occurrence data are available for this variant.
PS3
No variant-specific functional assay data were identified for c.2096A>T in the VCEP functional assay documentation (Functional-assay-SVI-documentation-MMR.xlsx) or in published literature.
PM5
No different missense variant at amino acid residue Asp699 has been classified as Pathogenic or Likely Pathogenic by this VCEP.
PP1
No co-segregation data are available for this variant.
PP4
No MSI or immunohistochemistry tumor data are available for patients carrying this variant.
Benign
BA1
The variant is absent from gnomAD v4 and does not meet the VCEP BA1 threshold of Grpmax filtering allele frequency ≥0.0028 (0.28%).
BS1
The variant is absent from gnomAD v4 and does not meet the VCEP BS1 threshold of Grpmax filtering allele frequency ≥0.00028 (0.028%).
BS2
No data are available regarding co-occurrence in trans with a known pathogenic PMS2 variant in a patient with colorectal cancer after age 45 without CMMRD features.
BS3
No variant-specific functional assay data demonstrating proficient MMR function are available for c.2096A>T.
BS4
No segregation data are available to assess lack of co-segregation with disease.
BP4
HCI MAPP/PP2 Prior probability for this missense variant is 0.8907, which does not meet the VCEP BP4_Supporting threshold of <0.11.
BP5
No tumor MSI or IHC data are available to assess whether tumors are MSS or show preserved MMR protein expression inconsistent with PMS2 pathogenicity.
BP7
BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 per the VCEP specification.
N/A · 12
PVS1 · PS4 · PM1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.969. BayesDel score = 0.419018. HCI prior probability for pathogenicity = 0.8907. MAPP score = 22.25. Custom PP2 score = 0.999.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PMS2, an endonuclease involved in DNA repair, is altered in various cancers.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 1 PMID not cited in assessment
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR