Variant classification summary

NM_000535.7:c.2515C>T

PMS2 · NP_000526.2:p.(His839Tyr) · NM_000535.7

GRCh37: chr7:6013104 G>A · GRCh38: chr7:5973473 G>A

Gene: PMS2 Transcript: NM_000535.7

Final call

VUS

PM2 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(His839Tyr)

gnomAD AF

1.351822662495843e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000535.7:c.2515C>T (p.His839Tyr) is a missense variant in PMS2 exon 15. It is extremely rare in population databases (gnomAD v4.1: 1/739,742 alleles, AF=1.35e-06), meeting PM2_Supporting under the InSiGHT PMS2 VCEP specification.

2

In silico predictions are indeterminate: HCI prior probability is 0.514, which falls between the VCEP PP3 (>0.68) and BP4 (<0.11) thresholds. SpliceAI predicts no splicing impact (max delta=0.00).

3

No variant-specific functional data, segregation data, de novo observations, or tumor pathology data are available. This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (VariationID: 1792458, criteria provided, single submitter).

4

With only PM2_Supporting met and no benign criteria met, this variant is classified as Uncertain Significance under the InSiGHT PMS2 VCEP v2.0 framework.

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 v2.0 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	Missense variant (NP_000526.2:p.His839Tyr); PVS1 applies only to null variants (nonsense, frameshift, canonical ±1/2 splice, initiation codon). Not applicable to missense substitutions.
PS1	Not met	No alternative nucleotide change encoding the same H839Y amino acid change has been established as Pathogenic by this VCEP. The reference codon is CAC; c.2515C>T is the only nucleotide substitution producing H839Y.
PS2	Not assessed	No de novo data available for this variant. PS2 requires confirmed maternity and paternity in a proband with MMR-deficient LS spectrum tumor.
PS3	Not assessed	No variant-specific functional data available. OncoKB reports unknown oncogenic effect. No publications with functional evidence for NM_000535.7:c.2515C>T were identified. The VCEP functional assay documentation does not include this variant.
PS4	N/A	PS4 is marked Not Applicable by the InSiGHT PMS2 VCEP specification.
PS5	N/A	PS5 is not included in the InSiGHT PMS2 VCEP specification.
PM1	N/A	PM1 is marked Not Applicable by the InSiGHT PMS2 VCEP specification.
PM2	Met	Extremely rare in gnomAD v4.1 (1/739,742 alleles; AF=1.35e-06), below the VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles). Absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v4
PM3	N/A	Recessive disorder data not applicable for PMS2; Lynch syndrome is autosomal dominant.
PM4	N/A	Missense variant; PM4 applies to protein length changes (in-frame deletions/insertions, stop-loss). Not applicable to missense substitutions.
PM5	Not met	No different missense change at codon 839 has been classified as Pathogenic or Likely Pathogenic by this VCEP. Other substitutions at this codon (c.2515C>A, p.H839N; c.2515C>G, p.H839D) have no established VCEP classification.
PM6	N/A	PM6 is marked Not Applicable by the InSiGHT PMS2 VCEP specification.
PP1	Not assessed	No co-segregation data available. PP1 requires combined Bayes Likelihood Ratio from pedigrees.
PP2	N/A	PP2 is marked Not Applicable by the InSiGHT PMS2 VCEP specification.
PP3	Not met	HCI prior probability for c.2515C>T is 0.514, which does not meet VCEP PP3 thresholds (>0.68 for supporting, >0.81 for moderate). SpliceAI predicts no splicing impact (max delta score=0.00). REVEL score 0.632 is not used by the PMS2 VCEP for PP3.	hci_prior spliceai
PP4	Not assessed	No patient phenotype, tumor MSI/IHC, or family history data available. PP4 requires MSI-H tumors or loss of MMR protein expression consistent with variant location.
PP5	N/A	PP5 is marked Not Applicable by the InSiGHT PMS2 VCEP specification.
BA1	Not met	gnomAD v4 allele frequency (AF=1.35e-06) is far below the VCEP BA1 threshold of ≥0.0028 (0.28%). This variant is not a common population polymorphism.	gnomad_v4
BS1	Not met	gnomAD v4 allele frequency (AF=1.35e-06) is below the VCEP BS1 threshold of ≥0.00028 (0.028%).	gnomad_v4
BS2	Not assessed	No co-occurrence or phase data available. BS2 requires observation in trans with a known pathogenic variant in a patient with CRC after age 45 without CMMRD features.
BS3	Not assessed	No variant-specific functional data demonstrating normal protein function. No calibrated functional assay data with odds favoring benign effect.
BS4	Not assessed	No co-segregation data available. BS4 requires Bayes Likelihood Ratio from pedigrees demonstrating lack of segregation with disease.
BP1	N/A	BP1 is marked Not Applicable by the InSiGHT PMS2 VCEP specification.
BP2	N/A	BP2 is marked Not Applicable by the InSiGHT PMS2 VCEP specification.
BP3	N/A	Missense variant; BP3 applies to in-frame deletions/insertions in repetitive regions. Not applicable to missense substitutions.
BP4	Not met	HCI prior probability 0.514 exceeds the VCEP BP4 threshold of <0.11. Multiple in silico predictors do not suggest a benign effect (REVEL=0.632; BayesDel=0.022). SpliceAI predicts no splicing impact (max delta=0.00).	hci_prior revel bayesdel spliceai
BP5	Not assessed	No tumor data available. BP5 requires observation of MSS tumors without loss of MMR protein expression, or BRAF V600E/MLH1 methylation with MSI-H.
BP6	N/A	BP6 is marked Not Applicable by the InSiGHT PMS2 VCEP specification.
BP7	N/A	Missense variant; BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. Not applicable to missense substitutions.

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