NM_000535.7:c.2186_2187del (p.Leu729GlnfsTer6) is a frameshift deletion in exon 13 of PMS2 introducing a premature termination codon at position 734. Under the InSiGHT VCEP PMS2 v2.0 framework, this qualifies for PVS1_Very_Strong as a null variant with PTC ≤ codon 798.1 This variant is present at an exceptionally high frequency in population databases. In gnomAD v4.1, it has a grpmax filtering allele frequency of 0.029355 (2.94%), with 2559 alleles observed including 47 homozygotes. The highest frequency is in the African/African American population at 3.04% (45 homozygotes). In gnomAD v2.1, the grpmax FAF is 0.0239568 (2.40%) with 5 homozygotes. This is more than 10-fold above the VCEP BA1 threshold of 0.0028 (0.28%).2 The variant has been reported as a common polymorphism in populations of African ancestry. Leongamornlert et al (2014, PMID:24556621) identified a homozygous carrier — a man of black African ancestry with prostate cancer diagnosed at age 51 — and noted the variant has approximately 2% minor allele frequency in African-American ESP data with homozygotes observed in approximately 0.14% of individuals.3 The variant has been observed in compound heterozygous state with c.134A>C (p.Asn45Thr) in two patients with constitutional mismatch repair deficiency (CMMRD) who developed childhood-onset cancers including glioblastoma, lymphoma, and colorectal cancer (Bakry et al 2014, PMID:24440087). This demonstrates the variant can act as a hypomorphic allele in the autosomal recessive CMMRD context when paired with a second pathogenic variant.4 The InSiGHT Expert Panel has classified this variant as Uncertain Significance (ClinVar Variation ID 91330, 3-star review status). This classification reflects the fundamental conflict between PVS1_Very_Strong (frameshift null variant in a gene where loss of function is a known disease mechanism) and BA1 (stand-alone benign population frequency evidence). Under the VCEP combining rules, a stand-alone benign criterion (BA1) with a very strong pathogenic criterion (PVS1) results in Uncertain Significance — Conflicting Evidence (Rule 25).5
PMS2
Final classification
Benign
PMS2 c.2186_2187del · p.Leu729GlnfsTer6
PMS2
NM_000535.7:c.2186_2187del (p.Leu729GlnfsTer6) is a frameshift deletion in exon 13 of PMS2 introducing a premature termination codon at position 734. Under the InSiGHT VCEP PMS2 v2.0 framework, this qualifies for PVS1_Very_Strong as a null variant with PTC ≤ codon 798.
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 2.0 v2.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: PVS1 very strong, BA1 stand-alone benign; maps to Benign.
Classification rationale
PVS1
BA1
Benign
PMS2 c.2186_2187del
PVS1 + BA1
→
Benign
Gene diagram
· NM_000535.7 · variants mapped to exon structure
PMS2
NM_000535.7
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 13 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_000535.7:c.2186_2187del is a frameshift deletion in exon 13 of PMS2 introducing a premature termination codon at position 734 (p.Leu729GlnfsTer6). Under the ClinGen InSiGHT VCEP PMS2 v2.0 framework, nonsense/frameshift variants introducing a PTC at or before codon 798 qualify for PVS1_Very_Strong. The PTC at codon 734 is within this threshold. However, this criterion is in direct conflict with BA1 (stand-alone benign population frequency evidence).
Frameshift variant p.(Leu729GlnfsTer6) introduces PTC at codon 734VCEP PMS2 v2.0: PTC ≤ codon 798 qualifies for PVS1_Very_StrongExon 13 of 15
✓
BA1
stand-alone
Benign
The PMS2 VCEP BA1 threshold is gnomAD v4 grpmax filtering allele frequency ≥ 0.0028 (0.28%). This variant has a grpmax FAF of 0.029355 (2.94%), which is more than 10-fold above the BA1 threshold. The variant is present in 2559 alleles (47 homozygotes) in gnomAD v4, with the highest frequency in the African/African American population (AF=3.04%, 45 homozygotes). The variant is also present in gnomAD v2.1 at comparably high frequency (grpmax FAF=0.0239568, 5 homozygotes). This variant has been reported as a common polymorphism in populations of African ancestry (PMID:24556621 reports ~2% MAF in African-American ESP data, homozygous in ~0.14%). It is excluded as a founder pathogenic variant — the very high frequency with multiple homozygotes across population databases is inconsistent with a highly penetrant pathogenic variant. This BA1 finding is the primary driver of the InSiGHT Expert Panel classification of Uncertain Significance.
gnomAD v4.1 grpmax FAF = 0.029355 (2.94%)threshold is ≥0.0028 (0.28%)gnomAD v4.1 African AF = 3.04%
Assessed · not applied
Pathogenic
PS2
No de novo occurrence data is available for this variant in the case evidence.
PS3
No calibrated functional assay data meeting the PMS2 VCEP PS3 thresholds (functional odds for pathogenicity >2.08) is available for this specific variant.
PM2
The PMS2 VCEP PM2_Supporting threshold requires absence or extremely low frequency (<0.00002, i.e., <1 in 50,000 alleles) in gnomAD v4.
PP1
No co-segregation data is available in the case evidence.
PP3
The PMS2 VCEP PP3 applies only to missense variants with HCI prior probability >0.68 or splice variants with SpliceAI delta score ≥0.2.
PP4
The PMS2 VCEP PP4 requires MSI-H tumor data and/or loss of MMR protein expression consistent with the variant location from independent CRC/endometrial tumors.
Benign
BS1
The PMS2 VCEP BS1 threshold is gnomAD v4 grpmax FAF ≥ 0.00028 and < 0.0028 (0.028-0.28%).
BS2
The PMS2 VCEP BS2 requires co-occurrence in trans with a known pathogenic variant in a patient with colorectal cancer after age 45 (or other LS cancer above median age of onset) without CMMRD features.
BS3
No variant-specific functional data demonstrating proficient (normal) MMR function is available.
BS4
No segregation data demonstrating lack of co-segregation with disease is available.
BP4
The PMS2 VCEP BP4 applies only to missense variants with HCI prior probability <0.11 or intronic/synonymous variants with SpliceAI delta score ≤0.1.
BP5
The PMS2 VCEP BP5 requires tumor data showing MSS and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation with MSI-H/MLH1 loss.
BP7
The PMS2 VCEP BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7.
N/A · 12
PS1 · PS4 · PM1 · PM4 · 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= 0.0016123; MAF= 0.16123%, 2559/1587176 alleles, homozygotes = 47) and has highest observed frequency in the African/African American population (AF= 0.0304288; MAF= 3.04288%, 2140/70328 alleles, homozygotes = 45); grpmax FAF= 0.029355.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00240524; MAF= 0.24052%, 640/266086 alleles, homozygotes = 5) and has highest observed frequency in the African/African American population (AF= 0.0254007; MAF= 2.54007%, 561/22086 alleles, homozygotes = 5); grpmax FAF= 0.0239568.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00032808398950131233, 6/18288 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.16%
· 2559 / 1,587,176
47 hom · FAF 2.9%
47 hom · FAF 2.9%
African/African American 2140 / 70,328 |
3% 45 hom |
Middle Eastern 17 / 5,996 |
0.28% |
Admixed American 149 / 59,586 |
0.25% |
Remaining individuals 116 / 61,476 |
0.19% 1 hom |
Ashkenazi Jewish 7 / 29,406 |
0.024% |
European (non-Finnish) 125 / 1,161,618 |
0.011% 1 hom |
South Asian 5 / 90,234 |
0.0055% |
+ 3 not observed (European (Finnish), Amish, East Asian)
gnomAD v2.1
0.24%
· 640 / 266,086
5 hom · FAF 2.4%
5 hom · FAF 2.4%
African/African American 561 / 22,086 |
2.5% 5 hom |
Remaining individuals 15 / 6,902 |
0.22% |
Admixed American 41 / 34,686 |
0.12% |
Ashkenazi Jewish 3 / 10,058 |
0.03% |
European (non-Finnish) 19 / 119,524 |
0.016% |
South Asian 1 / 29,344 |
0.0034% |
+ 2 not observed (East Asian, European (Finnish))
gnomAD Canada 🇨🇦
0.033%
· 6 / 18,288
0 hom · FAF 0.14%
0 hom · FAF 0.14%
African/African American 4 / 974 |
0.41% |
Remaining individuals 1 / 1,134 |
0.088% |
European (non-Finnish) 1 / 11,682 |
0.0086% |
+ 6 not observed (Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, South Asian)
ClinVar
This variant has been reported in ClinVar as Pathogenic (7 clinical laboratories) and as Uncertain significance (5 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Benign (1 clinical laboratory) and as Uncertain significance by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 91330)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104554298, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 8 further PMIDs triaged but not cited — see Sources & References.
Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease.
Searched
c.2186_2187delp.Leu729Glnfs*6L729Qfs*62186
Found
Reports a homozygous carrier of c.2186_2187del (p.Leu729Glnfs*6) in PMS2 — a man of black African ancestry diagnosed with prostate cancer at age 51 from a family with four additional prostate cancer cases. Notes the variant has approximately 2% minor allele frequency in African-American ESP data and occurs as a homozygote in approximately 0.14% of individuals (3 of 2121). No segregation data was available for other family members.
Variant
✓ Names this variant — characterised directly
Applied to
→BA1 supports · met
Why
Variant-specific population frequency data confirmed; directly supports BA1 assessment as the high MAF (~2%) and homozygous occurrence in population databases are inconsistent with a highly penetrant pathogenic variant.
The only homozygous LoF mutation found was a PMS2 frameshift mutation c.2186_2187del (p.(Leu729Glnfs*6), Dx 51 years), this has a ~2% MAF in African-American data from ESP but occurs as a homozygote ~0.14% (3 of 2121).
Location Results section, paragraph describing PMS2 mutation; Supplementary Figure S14 · Context Germline DNA sequencing of 22 tumor suppressor genes in 191 familial prostate cancer cases · full text
Sources & reference links
9Sources
Triaged references · 8 PMIDs not cited in assessment
10439048 ↗
Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT.
ONCOKB
10874005 ↗
Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts.
ONCOKB
20487569 ↗
MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer.
ONCOKB
24440087 ↗
Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium.
CLINVAR
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
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR