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.1 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.2 SpliceAI predicts no splicing impact (max delta = 0.00), satisfying the VCEP BP4_Supporting criterion for synonymous variants (delta ≤ 0.1).3 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.4 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).5 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.
PMS2
Final classification
Likely Benign
PMS2 c.2265C>T · p.Ile755=
PMS2
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.
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: matched Rule19 (Benign.Supporting >=2) with applied criteria: BS1 strong, BS3 supporting, BP4 supporting, BP7 supporting; maps to Likely Benign.
Classification rationale
BS1BS3BP4BP7
Likely Benign
PMS2 c.2265C>T
BS1 + BS3 + BP4 + BP7
→
Likely Benign
Gene diagram
· NM_000535.7 · variants mapped to exon structure
PMS2
NM_000535.7
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 10 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
strong
Benign
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 v4.1: AF=5.74e-05 (92/1602058 alleles
✓
BS3
supporting
review
Benign
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 max delta = 0.00 — no predicted splicing impact. Exploratory agent confirmed ClinGen PMS2 VCEP classification as Benign with BS3.
✓
BP4
supporting
Benign
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 max delta = 0.00 ≤ 0.1 — meets VCEP BP4_Supporting threshold for synonymous variants.
✓
BP7
supporting
Benign
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.
Synonymous variant p.(Ile755=) in exon 13 at c.2265. SpliceAI max delta = 0.00. VCEP BP7 applies to synonymous variants within the -21/+7 splice region with no predicted splicing impact.
Assessed · not applied
Pathogenic
PS2
No de novo occurrence data (with confirmed paternity/maternity) reported for NM_000535.7:c.2265C>T in any affected individual.
PS3
The PMS2 VCEP BS3 rule includes synonymous variants with no mRNA aberration by lab assays with NMD inhibition.
PM2
VCEP PM2_Supporting requires allele frequency < 0.00002 (<1 in 50,000 alleles) in gnomAD v4.
PP1
No co-segregation data available for this variant.
PP3
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.
PP4
No CRC/endometrial tumor MSI-H or MMR protein expression data reported for individuals carrying this variant.
Benign
BA1
VCEP BA1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0028 (0.28%).
BS2
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.
BS4
No lack-of-segregation data available for this variant.
BP5
No tumor MSS/IHC data or BRAF V600E/MLH1 methylation data reported for individuals carrying this variant.
N/A · 12
PVS1 · PS1 · PS4 · PM1 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.74261e-05; MAF= 0.00574%, 92/1602058 alleles, homozygotes = 5) and has highest observed frequency in the South Asian population (AF= 0.000773036; MAF= 0.07730%, 70/90552 alleles, homozygotes = 5); grpmax FAF= 0.00062731.
v2.1
This variant is present in gnomAD v2.1 (AF= 8.82301e-05; MAF= 0.00882%, 22/249348 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.00065647; MAF= 0.06565%, 20/30466 alleles, homozygotes = 2); grpmax FAF= 0.00043432.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0057%
· 92 / 1,602,058
5 hom · FAF 0.063%
5 hom · FAF 0.063%
South Asian 70 / 90,552 |
0.077% 5 hom |
Middle Eastern 1 / 6,028 |
0.017% |
Remaining individuals 5 / 61,966 |
0.0081% |
Ashkenazi Jewish 1 / 29,448 |
0.0034% |
European (non-Finnish) 15 / 1,172,156 |
0.0013% |
+ 5 not observed (Admixed American, European (Finnish), Amish, East Asian, African/African American)
gnomAD v2.1
0.0088%
· 22 / 249,348
2 hom · FAF 0.043%
2 hom · FAF 0.043%
South Asian 20 / 30,466 |
0.066% 2 hom |
European (non-Finnish) 2 / 112,296 |
0.0018% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Benign (4 clinical laboratories). (ClinVarID = 220273)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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
Triaged references · 9 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
23788249 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
CLINVAR
25356965 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
27854360 ↗
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
CLINVAR
34012068 ↗
ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR