Variant classification summary

NM_000535.7:c.2096A>T

PMS2 · NP_000526.2:p.(Asp699Val) · NM_000535.7

GRCh37: chr7:6022533 T>A · GRCh38: chr7:5982902 T>A

Gene: PMS2 Transcript: NM_000535.7

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Asp699Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2_Supporting is met: the variant is absent from gnomAD v4.1, meeting the VCEP threshold of <0.00002 allele frequency.

2

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.

3

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).

4

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.

Final determination: No criteria-combination rule matched the adjudicated criteria 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 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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: this is a missense substitution variant, not a null variant (nonsense, frameshift, or canonical ±1,2 splice site) per the PMS2 VCEP PVS1 rules.	cspec
PS1	Not met	No alternative nucleotide change at codon 699 producing p.(Asp699Val) has been established as Pathogenic by this VCEP. The only single-nucleotide variant producing Asp699Val is c.2096A>T itself.	cspec vcep_hci_priors_pms2
PS2	Not met	No de novo occurrence data are available for this variant. PS2 requires at least 0.5 de novo points per the VCEP framework.	cspec
PS3	Not assessed	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.	vcep_functional_assay_svi_documentation_mmr
PS4	N/A	VCEP designates PS4 as Not Applicable for PMS2.	cspec
PS5	N/A	VCEP designates PS5 as Not Applicable for PMS2.	cspec
PM1	N/A	VCEP designates PM1 as Not Applicable for PMS2.	cspec
PM2	Met	The variant is absent from gnomAD v4.1, meeting the VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles).	gnomad_v4 gnomad_v2 gnomad_canada cspec
PM5	Not met	No different missense variant at amino acid residue Asp699 has been classified as Pathogenic or Likely Pathogenic by this VCEP. PM5 requires a known P/LP missense change at the same residue.	cspec vcep_vcep_pilot_variants_mmr pm5_candidates
PM6	N/A	VCEP designates PM6 as Not Applicable for PMS2.	cspec
PP1	Not assessed	No co-segregation data are available for this variant.	cspec
PP2	N/A	VCEP designates PP2 as Not Applicable for PMS2.	cspec
PP3	Met	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 vcep_hci_priors_pms2 cspec
PP4	Not assessed	No MSI or immunohistochemistry tumor data are available for patients carrying this variant. PP4 requires MSI-H tumors and/or loss of MMR protein expression consistent with PMS2.	cspec
PP5	N/A	VCEP designates PP5 as Not Applicable for PMS2.	cspec
BA1	Not met	The variant is absent from gnomAD v4 and does not meet the VCEP BA1 threshold of Grpmax filtering allele frequency ≥0.0028 (0.28%).	gnomad_v4 cspec
BS1	Not met	The variant is absent from gnomAD v4 and does not meet the VCEP BS1 threshold of Grpmax filtering allele frequency ≥0.00028 (0.028%).	gnomad_v4 cspec
BS2	Not assessed	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.	cspec
BS3	Not assessed	No variant-specific functional assay data demonstrating proficient MMR function are available for c.2096A>T.	vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	No segregation data are available to assess lack of co-segregation with disease.	cspec
BP1	N/A	VCEP designates BP1 as Not Applicable for PMS2.	cspec
BP2	N/A	VCEP designates BP2 as Not Applicable for PMS2.	cspec
BP4	Not met	HCI MAPP/PP2 Prior probability for this missense variant is 0.8907, which does not meet the VCEP BP4_Supporting threshold of <0.11. SpliceAI delta score is 0.00, but the SpliceAI-based BP4 rule applies only to intronic and synonymous variants per the VCEP specification.	hci_prior spliceai cspec
BP5	Not assessed	No tumor MSI or IHC data are available to assess whether tumors are MSS or show preserved MMR protein expression inconsistent with PMS2 pathogenicity.	cspec
BP6	N/A	VCEP designates BP6 as Not Applicable for PMS2.	cspec
BP7	Not met	BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 per the VCEP specification. c.2096A>T is a missense variant (p.Asp699Val) and does not qualify.	cspec
BP3	N/A	Skipped per instruction. VCEP designates BP3 as Not Applicable.	cspec
PM3	N/A	Skipped per instruction.
PM4	N/A	Skipped per instruction.

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