Variant classification summary

NM_000535.7:c.2186_2187del

PMS2 · NP_000526.2:p.(Leu729GlnfsTer6) · NM_000535.7

GRCh37: chr7:6018314 TGA>T · GRCh38: chr7:5978683 TGA>T

Gene: PMS2 Transcript: NM_000535.7

Final call

Benign

PVS1 very strong BA1 stand-alone benign

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Leu729GlnfsTer6)

gnomAD AF

0.0016122975649833415 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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%).

3

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.

4

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.

5

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).

Final determination: Rule17 in the 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 is satisfied by the adjudicated criteria, so the variant is classified as 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	Met	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).	cspec
PS1	N/A	PS1 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.
PS2	Not met	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.
PS3	Not met	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.	oncokb
PS4	N/A	The 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.'
PS5	N/A	PS5 is not defined in the PMS2 VCEP v2.0 criteria set and is not used for MMR variant classification.
PM1	N/A	The 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.'
PM2	Not met	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.	gnomad_v4
PM4	N/A	The 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.
PM5	N/A	PM5 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.
PM6	N/A	The PMS2 VCEP explicitly states PM6 is not applicable for MMR variant classification.
PP1	Not met	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.
PP2	N/A	The PMS2 VCEP explicitly states PP2 is not applicable: 'Missense variant in a gene with low rate of benign missense changes does not apply.'
PP3	Not met	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.	spliceai
PP4	Not met	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.
PP5	N/A	The PMS2 VCEP explicitly states PP5 is 'Not Applicable for this VCEP' as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BA1	Met	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 gnomad_v2 PMID:24556621
BS1	Not met	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.	gnomad_v4
BS2	Not met	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.	PMID:24440087
BS3	Not met	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.
BS4	Not met	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.
BP1	N/A	The PMS2 VCEP explicitly states BP1 is not applicable: 'Missense variant in a gene where only loss of function causes disease is not applicable.'
BP2	N/A	The PMS2 VCEP explicitly states BP2 is not applicable: BS2 is used instead.
BP3	N/A	The 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.
BP4	Not met	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.	spliceai
BP5	Not met	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.
BP6	N/A	The PMS2 VCEP explicitly states BP6 is 'Not Applicable for this VCEP' as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BP7	Not met	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.

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