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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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