Variant classification summary

NM_000535.7:c.2265C>T

PMS2 · NP_000526.2:p.(Ile755=) · NM_000535.7

GRCh37: chr7:6018237 G>A · GRCh38: chr7:5978606 G>A

Gene: PMS2 Transcript: NM_000535.7

Final call

Likely Benign

BS1 strong BS3 supporting BP4 supporting BP7 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Ile755=)

gnomAD AF

5.7426135633042e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000535.7:c.2265C>T is a synonymous variant in PMS2 (p.Ile755=) with SpliceAI delta score of 0.00, predicting no splicing impact.

2

This variant is present in gnomAD v4.1 at an allele frequency of 5.74e-05 (92/1,602,058 alleles) with 5 homozygotes, and gnomAD v2.1 at 8.82e-05 (22/249,348 alleles) with 2 homozygotes. The gnomAD v4.1 grpmax filtering allele frequency is 0.00062731 (0.0627%), meeting the PMS2 VCEP BS1 threshold (≥0.028%, <0.28%) at Strong strength.

3

SpliceAI predicts no splicing impact (max delta = 0.00), satisfying the VCEP BP4_Supporting criterion for synonymous variants (delta ≤ 0.1).

4

As a synonymous variant located within the splice region at position c.2265 (exon 13, donor -10) with no predicted splicing impact, the VCEP BP7_Supporting criterion is met.

5

The PMS2 VCEP has classified this variant as Benign (ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications v2.0.0). Nine clinical laboratories in ClinVar report this variant as Likely benign (5) or Benign (4).

6

Applying the PMS2 VCEP v2.0.0 ACMG/AMP combination rules: BS1 (Strong) + BP4 (Supporting) + BP7 (Supporting) yields a classification of Likely Benign per Rule 18 (1 Benign Strong + 1 Benign Supporting → Likely Benign). The variant is classified as Likely Benign.

Final determination: Rule19 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 Likely Benign.

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	Synonymous variant (p.Ile755=) does not introduce a premature termination codon, frameshift, or affect canonical ±1,2 splice sites. SpliceAI delta score is 0.00, confirming no cryptic splice impact. Does not meet any PVS1 bucket under PMS2 VCEP v2.0.0.	spliceai pvs1_variant_assessment
PS1	N/A	Synonymous variant; PS1 under PMS2 VCEP v2.0.0 requires a different nucleotide change encoding the same amino acid change previously established as pathogenic by this VCEP. A synonymous change does not produce a missense substitution at the protein level.
PS2	Not assessed	No de novo occurrence data (with confirmed paternity/maternity) reported for NM_000535.7:c.2265C>T in any affected individual. Exploratory literature search found no de novo reports.
PS3	Not assessed	The PMS2 VCEP BS3 rule includes synonymous variants with no mRNA aberration by lab assays with NMD inhibition. SpliceAI delta=0.00 supports no splicing impact, but direct laboratory functional assay data (e.g., minigene splicing assay, RT-PCR with NMD inhibition) for this specific variant were not reviewed in full-text. The ClinGen PMS2 VCEP has classified this variant as Benign citing BS3; deep-dive recommended PMIDs include Wielders et al. 2015 (PMID:25985013) and van der Klift et al. 2019 (PMID:30998989).	spliceai
PS4	N/A	PS4 is marked Not Applicable by the PMS2 VCEP v2.0.0.
PS5	N/A	PS5 is not a criterion defined in the PMS2 VCEP v2.0.0 framework.
PM1	N/A	PM1 is marked Not Applicable by the PMS2 VCEP v2.0.0.
PM2	Not met	VCEP PM2_Supporting requires allele frequency < 0.00002 (<1 in 50,000 alleles) in gnomAD v4. This variant is present in gnomAD v4.1 at AF = 5.74e-05 (92/1,602,058 alleles, including 5 homozygotes), exceeding the PM2 threshold. The variant is also present in gnomAD v2.1 at AF = 8.82e-05 (22/249,348 alleles, 2 homozygotes).	gnomad_v4 gnomad_v2
PM5	N/A	Synonymous variant (p.Ile755=); PM5 requires a missense change at an amino acid residue where a different missense change has been classified as pathogenic/likely pathogenic by this VCEP. PM5 candidates module confirmed variant class is not missense-like.	pm5_candidates
PM6	N/A	PM6 is marked Not Applicable by the PMS2 VCEP v2.0.0.
PP1	Not assessed	No co-segregation data available for this variant. The variant is present at appreciable population frequency (5 homozygotes in gnomAD v4.1), making co-segregation analysis unlikely to be informative for pathogenicity.	gnomad_v4
PP2	N/A	PP2 is marked Not Applicable by the PMS2 VCEP v2.0.0.
PP3	Not met	VCEP PP3 for missense variants requires HCI prior probability >0.68; c.2265C>T is a synonymous variant and is not present in the PMS2 HCI priors table. For non-canonical splice variants, PP3_Supporting requires SpliceAI delta ≥ 0.2; this variant has SpliceAI max delta = 0.00. No computational evidence supports a pathogenic effect.	spliceai
PP4	Not assessed	No CRC/endometrial tumor MSI-H or MMR protein expression data reported for individuals carrying this variant. Exploratory search found no tumor phenotype data.
PP5	N/A	PP5 is marked Not Applicable by the PMS2 VCEP v2.0.0.
BA1	Not met	VCEP BA1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0028 (0.28%). The variant has gnomAD v4.1 grpmax FAF = 0.00062731 (0.0627%), which is below the BA1 threshold. The variant is too rare in the general population to qualify as a stand-alone benign criterion.	gnomad_v4
BS1	Met	VCEP BS1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.00028 and < 0.0028 (0.028–0.28%). This variant has gnomAD v4.1 grpmax FAF = 0.00062731 (0.0627%), which falls within the BS1 range. The variant is also observed with 5 homozygotes in gnomAD v4.1 and 2 homozygotes in gnomAD v2.1, providing additional evidence against a highly penetrant pathogenic role. The variant is not a recognized founder pathogenic variant.	gnomad_v4 gnomad_v2
BS2	Not assessed	No observation of this variant in trans with a known pathogenic PMS2 variant in a patient with colorectal cancer after age 45 (or other LS cancer above median onset age) without CMMRD features has been reported. Confirmation of phase requires parental/offspring testing.
BS3	Met	SpliceAI predicts no splicing impact (max delta = 0.00) for this synonymous variant, consistent with normal mRNA processing. The PMS2 VCEP has classified this variant as Benign citing BS3 evidence. The VCEP BS3 rule for synonymous variants requires laboratory assays with NMD inhibition showing no mRNA aberration; the SpliceAI prediction of delta=0.00 provides computational support, though direct review of functional assay data (PMID:25985013, PMID:30998989) is recommended for upgrade to BS3_Strong.	spliceai
BS4	Not assessed	No lack-of-segregation data available for this variant. BS4 requires pedigrees with combined Bayes Likelihood Ratio demonstrating lack of co-segregation with disease.
BP1	N/A	BP1 is marked Not Applicable by the PMS2 VCEP v2.0.0.
BP2	N/A	BP2 is marked Not Applicable by the PMS2 VCEP v2.0.0.
BP3	N/A	Skipped per instructions — trivially not_applicable (in-frame indels only).
BP4	Met	VCEP BP4 rule for intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score ≤ 0.1. This variant has SpliceAI max delta = 0.00, meeting the BP4_Supporting threshold. REVEL and BayesDel scores are not available for this synonymous variant, as expected.	spliceai
BP5	Not assessed	No tumor MSS/IHC data or BRAF V600E/MLH1 methylation data reported for individuals carrying this variant. BP5 requires tumor evidence inconsistent with a pathogenic role (MSS tumors, intact MMR protein expression, or BRAF/MLH1 methylation in MSI-H tumors).
BP6	N/A	BP6 is marked Not Applicable by the PMS2 VCEP v2.0.0.
BP7	Met	Synonymous variant (p.Ile755=) at c.2265 in exon 13 of PMS2 (c.2175–2275). The variant lies at position -10 from the donor splice site, which is within the VCEP BP7 region (at or beyond -21 from the donor). SpliceAI delta = 0.00 confirms no predicted splicing impact. The ClinGen PMS2 VCEP classified this variant as Benign and applied BP7. Per VCEP rules, variants may satisfy both BP7 and BP4.	spliceai

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