PMS2c.2186_2187delBenign

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Variant interpretation report

PMS2 c.2186_2187del, p.(Leu729GlnfsTer6)

NM_000535.7:c.2186_2187del NP_000526.2:p.(Leu729GlnfsTer6) View identifiers

Classification

Benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.

Benign.A benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PMS2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 stand alone (benign) · 1 very strong (pathogenic)
Expert rules: ClinGen PMS2 VCEP v2.0
Other laboratories (ClinVar): 7 Pathogenic · 5 Uncertain significance · 3 Likely pathogenic · 1 Benign
Pipeline record: 28 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): 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).
BA1 (stand alone): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is ClinGen PMS2 VCEP v2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1

Pathogenic criteria applied · 1

PVS1Very strong

PVS1 · very strong

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).

Benign criteria applied · 1

BA1Stand alone

BA1 · stand alone

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.

Recorded classification: Benign

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

2,559 / 1,587,176 alleles

gnomAD v4.1: 2,559 / 1,587,176 alleles. Recorded AF 0.0016123. Recorded homozygote count 47.

gnomAD 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.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00032808398950131233, 6/18288 alleles, homozygotes = 0).

Applied · BA1 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

16 reported laboratory submissions

7 Pathogenic · 5 Uncertain significance · 3 Likely pathogenic · 1 Benign. ClinVar API review status: reviewed by expert panel.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV104554298, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen PMS2 VCEP v2.0, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 13 not met · 0 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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%).

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.

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.

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).

Met · 2

PVS1 Very strongNM_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). Details ▾Hide ▴

Evidence considered

Frameshift variant p.(Leu729GlnfsTer6) introduces PTC at codon 734
VCEP PMS2 v2.0: PTC ≤ codon 798 qualifies for PVS1_Very_Strong
Exon 13 of 15
NMD predicted

Sources

cspec ↗

BA1 Stand aloneThe 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. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 0.029355 (2.94%)
threshold is ≥0.0028 (0.28%)
gnomAD v4.1 African AF = 3.04%
45 homozygotes
gnomAD v2.1 grpmax FAF = 0.0239568 (2.40%)
5 homozygotes
PMID:24556621: homozygous in a man of black African ancestry
~2% MAF in African-American ESP
homozygous in ~0.14%

Sources

gnomad_v4 ↗gnomad_v2 ↗PMID:24556621 ↗

Not met · 13 · evaluated, threshold not reached

PS2 No de novo occurrence data is available for this variant in the case evidence. The PMS2 VCEP requires confirmed maternity and paternity with an MMR-deficient LS spectrum tumor for de novo point assignment. Details ▾Hide ▴

Still missing

No de novo reports identified for this variant

PS3 No calibrated functional assay data meeting the PMS2 VCEP PS3 thresholds (functional odds for pathogenicity >2.08) is available for this specific variant. OncoKB curates a 'Likely Loss-of-function' label, but this is not a calibrated functional assay and does not satisfy VCEP PS3 requirements. The variant has not been directly tested in any of the calibrated MMR functional assays from the VCEP assay documentation. Details ▾Hide ▴

Evidence considered

OncoKB Likely Loss-of-function label (curated inference
not experimental data)
No variant-specific functional assay results identified in literature

Still missing

No variant-specific functional assay data from calibrated MMR assays

Sources

oncokb ↗

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. This variant has a gnomAD v4 allele frequency of 0.0016123 (2559/1587176 alleles, 47 homozygotes), far exceeding the PM2 threshold. PM2 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: AF=0.0016123 (2559/1587176 alleles
47 homozygotes)
grpmax FAF=0.029355 (African: AF=3.04%
45 homozygotes)
gnomAD v2.1: AF=0.00240524 (640/266086 alleles
5 homozygotes)

Sources

gnomad_v4 ↗

PP1 No co-segregation data is available in the case evidence. The PMS2 VCEP requires pedigree analysis with combined Bayes Likelihood Ratio from COOL (COsegregation OnLine) for PP1 application. Details ▾Hide ▴

Still missing

No segregation data available

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. This is a frameshift deletion — HCI prior lookup is not applicable for non-substitutions, and SpliceAI max delta score is 0.00, indicating no predicted splice impact. PP3 is not met. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no predicted splice impact)
HCI prior not applicable for frameshift variants
REVEL/BayesDel not applicable for non-SNV

Sources

spliceai ↗

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. No tumor MSI/IHC data is available in the case evidence for this variant. Details ▾Hide ▴

Still missing

No tumor MSI/IHC data available

BS1 The PMS2 VCEP BS1 threshold is gnomAD v4 grpmax FAF ≥ 0.00028 and < 0.0028 (0.028-0.28%). This variant has a grpmax FAF of 0.029355 (2.94%), which exceeds the BS1 upper bound. The variant frequency instead satisfies BA1 (stand-alone benign), which subsumes BS1 at higher frequencies. Details ▾Hide ▴

Evidence considered

gnomAD v4 grpmax FAF = 0.029355 exceeds BS1 range (<0.0028)
Frequency captured by BA1 instead

Sources

gnomad_v4 ↗

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. The variant has been observed in compound heterozygous state with c.134A>C (p.Asn45Thr) in two CMMRD patients (PMID:24440087), but these patients had childhood-onset cancers with CMMRD features and do not satisfy the BS2 criteria (which requires late-onset LS without CMMRD). No BS2-qualifying cases are available. Details ▾Hide ▴

Evidence considered

PMID:24440087: compound heterozygous with c.134A>C (p.Asn45Thr) in two CMMRD patients with childhood cancers
These CMMRD patients do not satisfy BS2 criteria (require late-onset CRC without CMMRD)

Still missing

No BS2-qualifying co-occurrence cases (late-onset CRC without CMMRD)

Sources

PMID:24440087 ↗

BS3 No variant-specific functional data demonstrating proficient (normal) MMR function is available. The PMS2 VCEP BS3 requires calibrated functional assays with functional odds for pathogenicity ≤0.05 for strong strength, or variant-specific proficient function per the MMR functional assay flowchart for supporting strength. No such evidence exists for this variant. Details ▾Hide ▴

Still missing

No variant-specific functional data demonstrating normal MMR function

BS4 No segregation data demonstrating lack of co-segregation with disease is available. The PMS2 VCEP BS4 requires pedigree analysis with combined Bayes Likelihood Ratio from COOL. Details ▾Hide ▴

Still missing

No segregation data 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. This is an exonic frameshift deletion and is not covered by either BP4 pathway. SpliceAI predicts no splice impact (max delta = 0.00), but BP4 is not applicable to frameshift variants. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00
BP4 pathways (HCI prior
SpliceAI) not applicable to frameshift variants

Sources

spliceai ↗

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. No tumor pathology data is available for this variant in the case evidence. Details ▾Hide ▴

Still missing

No tumor MSS/IHC data available

BP7 The PMS2 VCEP BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7. This is an exonic frameshift deletion and does not meet BP7 criteria. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 under the PMS2 VCEP applies only to missense substitutions encoding the same amino acid change as an established pathogenic variant, or splice variants affecting the same non-canonical splice nucleotide. This is a frameshift deletion and does not meet either condition. Details ▾Hide ▴

No further detail was recorded.

PS4 VCEPThe PMS2 VCEP explicitly states PS4 is not applicable: 'Due to the availability of tumor IHC data for variant classification (see PP4), PS4 has not been utilized for MMR variant classification using proband counting.' Details ▾Hide ▴

No further detail was recorded.

PM1 VCEPThe PMS2 VCEP explicitly states PM1 is not applicable: 'There are no recognized mutational hot spots that could be used for classification purposes. While there are functional domains in the MMR genes, the distribution of pathogenic variants is generalized over all the domains.' Details ▾Hide ▴

No further detail was recorded.

PM4 VCEPThe PMS2 VCEP explicitly states PM4 is not applicable: 'Protein length change from an in-frame variant is not used due to lack of evidence.' This is a frameshift (out-of-frame) deletion, not an in-frame change, further confirming non-applicability. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 under the PMS2 VCEP applies only to missense changes at an amino acid residue where a different missense change has been classified as pathogenic. This variant is a frameshift deletion, not a missense substitution, and is not eligible for PM5. Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPThe PMS2 VCEP explicitly states PM6 is not applicable for MMR variant classification. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPThe PMS2 VCEP explicitly states PP2 is not applicable: 'Missense variant in a gene with low rate of benign missense changes does not apply.' Details ▾Hide ▴

No further detail was recorded.

PP5 VCEPThe PMS2 VCEP explicitly states PP5 is 'Not Applicable for this VCEP' as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPThe PMS2 VCEP explicitly states BP1 is not applicable: 'Missense variant in a gene where only loss of function causes disease is not applicable.' Details ▾Hide ▴

No further detail was recorded.

BP2 VCEPThe PMS2 VCEP explicitly states BP2 is not applicable: BS2 is used instead. Details ▾Hide ▴

No further detail was recorded.

BP3 VCEPThe PMS2 VCEP explicitly states BP3 is not applicable: 'In-frame deletions/insertions in a repetitive region without a known function is not used.' This is a frameshift deletion, further confirming non-applicability. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPThe PMS2 VCEP explicitly states BP6 is 'Not Applicable for this VCEP' as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not defined in the PMS2 VCEP v2.0 criteria set and is not used for MMR variant classification. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: PMS2
Transcript: NM_000535.7
Coding (HGVS c.): NM_000535.7:c.2186_2187del
Protein (HGVS p.): NP_000526.2:p.(Leu729GlnfsTer6)
GRCh38: chr7:5978683 TGA>T
GRCh37: chr7:6018314 TGA>T
ClinVar: 91330
COSMIC: COSV104554298

Gene diagram

Every interpreted variant in PMS2, mapped onto the exon structure of NM_000535.7. Select a row to find it on the plot.

PMS2NM_000535.7

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in PMS2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 2,559 / 1,587,176 alleles AF 0.00161 · 47 homozygotes · FAF 0.0294

gnomAD v2.1 640 / 266,086 alleles AF 0.00241 · 5 homozygotes · FAF 0.024

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.0016 · 2559 / 1,587,176 alleles · 47 hom · FAF 0.029

African/African American2140 / 70,328	0.0345 hom
Middle Eastern17 / 5,996	0.0028
Admixed American149 / 59,586	0.0025
Remaining individuals116 / 61,476	0.00191 hom
Ashkenazi Jewish7 / 29,406	0.00024
European (non-Finnish)125 / 1,161,618	0.000111 hom
South Asian5 / 90,234	5.5e-05

0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, East Asian.

gnomAD v2.1

AF 0.0024 · 640 / 266,086 alleles · 5 hom · FAF 0.024

African/African American561 / 22,086	0.0255 hom
Remaining individuals15 / 6,902	0.0022
Admixed American41 / 34,686	0.0012
Ashkenazi Jewish3 / 10,058	0.0003
European (non-Finnish)19 / 119,524	0.00016
South Asian1 / 29,344	3.4e-05

0 alternate alleles recorded in 2 other groups: East Asian, European (Finnish).

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD 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.

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00032808398950131233, 6/18288 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +6 bp

0.000

SpliceAI acceptor gainat +45 bp

0.000

SpliceAI donor lossat +145 bp

0.000

SpliceAI donor gainat +250 bp

0.000

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta = 0.00 (no predicted splice impact)
HCI prior not applicable for frameshift variants
REVEL/BayesDel not applicable for non-SNV

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.00
BP4 pathways (HCI prior
SpliceAI) not applicable to frameshift variants

Sources

spliceai ↗

BP7 The PMS2 VCEP BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7. This is an exonic frameshift deletion and does not meet BP7 criteria. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

9 paper records listed. 1 cited in the classification.

Cited in the classification

Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease.

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.
→ BA1 Names this variant
PMID 24556621 ↗
Source detail

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

Other recorded publications

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.

Studies PMS2 knockout mice and their sensitivity to MNU-induced thymic lymphoma. This is a gene-level functional study using Pms2-deficient mice and does not examine or mention NM_000535.7:c.2186_2187del or any specific human PMS2 variant.
Does not name this variant
PMID 10439048 ↗
Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts.

Compares mutagenesis patterns in PMS2- and MSH2-deficient mice using mutation detection reporter transgenic mice. Gene-level study of MMR deficiency; does not mention NM_000535.7:c.2186_2187del or any specific human PMS2 variant.
Does not name this variant
PMID 10874005 ↗
Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha.

Investigates MLH1-PMS2 dimerization and its role in nuclear localization of MutLalpha. Discusses PMS2 at the gene/protein level but does not mention NM_000535.7:c.2186_2187del or any specific PMS2 variant.
Does not name this variant
PMID 12697830 ↗
Two PMS2 mutations in a Turcot syndrome family with small bowel cancers.

Reports two PMS2 mutations in a Turcot syndrome family with small bowel cancers. Discusses PMS2 mutations in the context of Turcot syndrome but does not mention NM_000535.7:c.2186_2187del.
Does not name this variant
PMID 16144131 ↗
MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer.

Reports MSH6 and PMS2 mutation-positive Australian Lynch syndrome families with novel mutations, cancer risk, and age of diagnosis of colorectal cancer. Does not mention NM_000535.7:c.2186_2187del.
Does not name this variant
PMID 20487569 ↗
Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium.

Bakry D et al. · 2014

Reports two CMMRD patients (MMR50, MMR51) compound heterozygous for c.2186-2187delTC (p.Leu729Glnfs*6) and c.134A>C (p.Asn45Thr) in PMS2. Both patients developed childhood-onset malignancies including glioblastoma at age 4, gastrointestinal polyposis, diffuse large B-cell lymphoma, oligodendroglioma, and rectal cancer. The p.Leu729Glnfs*6 variant was classified as Pathogenic in the study's annotation.
Names this variant
PMID 24440087 ↗
Quoted passage
PMS2 / c.2186-2187delTC/ c.134A > C / Comp Het / Pathogenic / Not found/ Pathogenic
Table, patients MMR50 and MMR51; variant listed in compound heterozygous state
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.

The ACMG/AMP standards and guidelines for interpretation of sequence variants. This is a background methods reference and does not discuss NM_000535.7:c.2186_2187del or any specific PMS2 variant.
Does not name this variant
PMID 25741868 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

No paper-specific finding is recorded.

PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 2,559 / 1,587,176 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 7 Pathogenic · 5 Uncertain significance · 3 Likely pathogenic · 1 Benign Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00032808398950131233, 6/18288 alleles, homozygotes = 0).

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

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104554298, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.