The PMS2 NM_000535.7:c.73C>T (NP_000526.2:p.(Gln25Ter)) nonsense variant has previously been reported in somatic cancers (COSMIC; COSV56151812, n = 1 time). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
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About PMS2
PMS2 is a DNA mismatch-repair protein that works with MLH1 to correct replication errors, including mismatches and small insertion or deletion loops. It acts as a tumor suppressor, and inherited loss of PMS2 function can cause Lynch syndrome and constitutional mismatch repair deficiency, increasing the risk of colorectal, endometrial, ovarian, urothelial, and other cancers. Loss of PMS2 function in tumors can cause hypermutation and microsatellite instability, which may make some cancers responsive to certain immunotherapies.
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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.
ACMG/AMP criteria under ClinGen PMS2 VCEP v2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 0 not met · 11 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 is met at very strong strength because the PMS2 nonsense variant introduces a premature termination codon at codon 25, within the VCEP-defined threshold of codon 798 or earlier.
PM4 and BP3 are not applicable under the PMS2 Version 2.0 VCEP specification.
All five requested criteria are not applicable under the PMS2 InSiGHT VCEP Version 2.0 rules: PS1 and PM5 are missense-specific, while PM1, PP2, and BP1 are explicitly marked Not Applicable.
No de novo, segregation, or non-segregation evidence can be assigned from the available variant-specific case data; PM6 is explicitly not applicable under the PMS2 VCEP framework.
PS4, PP5, and BP6 are not usable under the governing PMS2 VCEP rules because PS4, PP5, and BP6 are marked not applicable.
PP4 and BP5 remain not assessed because the available evidence lacks the patient-specific tumor and phenotype findings required by their VCEP rules.
All three requested computational criteria are not applicable because the variant is a nonsense coding change, while the VCEP scopes PP3/BP4/BP7 to missense, non-canonical splice, intronic, or synonymous variants as specified above.
PM2 Supporting is met because the gnomAD v4.1 total allele frequency is below the VCEP threshold.
BA1 and BS1 cannot be directly assessed because the required gnomAD v4 Grpmax filtering allele frequency is unavailable.
BS2 cannot be assessed because the required in-trans clinical co-occurrence and phase evidence are absent.
No criteria match.
Met · 2
PVS1Very strongVCEPMet, very strong: the PMS2 nonsense variant creates a premature stop at codon 25, within the VCEP threshold of codon 798 or earlier.
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Reasoning
NM_000535.7:c.73C>T is a nonsense variant producing NP_000526.2:p.(Gln25Ter) (p.Q25*) in PMS2 exon 2. The variant introduces a premature termination codon at codon 25, which is at or before codon 798, and therefore meets the VCEP's full-strength PVS1 rule for PMS2 nonsense variants. The VCEP pilot-variant table was searched for c.73C>T, p.Gln25Ter, and p.Q25*; no exact entry was found. The converted PVS1_DecisionTree_MMR.pdf text contains only a page header, so no additional variant-specific entry could be retrieved from that file.
VCEP rule
Nonsense/frameshift variant introducing Premature Termination Codon (PTC)<sup>a </sup> ≤ codon 798 in _PMS2_. Refer to Appendix for details.
Evidence considered
Case variant facts: NM_000535.7:c.73C>T, NP_000526.2:p.(Gln25Ter)/p.(Q25*), nonsense consequence, PMS2 exon 2.
The VCEP PVS1 rule states: Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 798 in PMS2. Refer to Appendix for details.
VCEP-pilot-variants---MMR.xlsx.txt was searched for c.73C>T, p.Gln25Ter, and p.Q25*; the matching variant was not listed.
PVS1_DecisionTree_MMR.pdf.txt was searched; the converted file contains only the page header and no body text.
Still missing
No exact c.73C>T, p.Gln25Ter, or p.Q25* entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
PVS1_DecisionTree_MMR.pdf.txt was searched, but its converted text contains only a page header and no searchable variant-specific entry.
PM2SupportingVCEPMet at Supporting: gnomAD v4 total AF 6.20819e-07 is below 0.00002, with 1 allele in 1,610,776 and no homozygotes.
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Reasoning
The InSiGHT PMS2 VCEP defines PM2 Supporting as an absent or extremely rare allele frequency below 0.00002 (<1 in 50,000 alleles) in gnomAD v4. The gnomAD v4.1 record for NM_000535.7:c.73C>T (p.Gln25Ter/p.Q25*) reports total AF 6.208187854797936e-07, 1 alternate allele among 1610776 alleles, and zero homozygotes. This is below the VCEP threshold, so PM2 Supporting is met. The governing VCEP pilot table was searched for c.73C>T, p.Gln25Ter, and p.Q25*, but no matching entry was found.
VCEP rule
Absent/extremely rare allele frequency \<0.00002 (\<1 in 50,000 alleles ) in gnomAD v4 dataset
Evidence considered
InSiGHT PMS2 VCEP CSPEC PM2 rule: absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in the gnomAD v4 dataset.
gnomAD v4.1 record for NM_000535.7:c.73C>T (p.Gln25Ter/p.Q25*): total AF 6.208187854797936e-07, 1/1610776 alleles, homozygotes 0; exome AC 1 and exome AN 1458496.
VCEP-pilot-variants---MMR.xlsx.txt was searched for c.73C>T, p.Gln25Ter, p.Q25*, Q25*, and Q25Ter; no matching row was found.
Still missing
No matching c.73C>T, p.Gln25Ter, or p.Q25* entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
PS2VCEPNot assessed: no proband-specific de novo finding, parental testing, or VCEP de novo point total is available for this variant.
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Reasoning
The VCEP evaluates PS2 by assigning de novo points and does not provide a de novo observation, parental testing result, maternity/paternity confirmation, or a proband-specific de novo point total for NM_000535.7:c.73C>T (p.Gln25Ter). Therefore no PS2 strength can be assigned.
VCEP rule
≥ 4 de novo points = Very Strong; 2 - 3.5 de novo points = Strong; 1 - 1.5 de novo points = Moderate; 0.5 de novo points = Supporting
Evidence considered
The case evidence contains no variant-specific de novo report, parental genotype results, maternity/paternity confirmation, or de novo point calculation for NM_000535.7:c.73C>T.
The reviewed variant-specific literature extracts do not mention NM_000535.7:c.73C>T or p.(Gln25Ter) and provide no de novo evidence.
Still missing
Documented de novo status in the proband
Parental testing establishing maternity and paternity
PS3VCEPNot assessed: no variant-specific functional assay result is available to compare with the VCEP's calibrated assay criteria or functional-assay flowchart.
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Reasoning
The governing PMS2 VCEP permits PS3 from calibrated functional assays or an MMR function defect interpreted through the VCEP functional-assay flowchart. The case contains no variant-specific functional result for NM_000535.7:c.73C>T (NP_000526.2:p.(Gln25Ter), p.(Q25*)). Exact searches for c.73C>T, p.Gln25Ter, and p.Q25* in Functional-assay-SVI-documentation-MMR.xlsx.txt and Functional-assay-flowchart.pdf.txt found no entry for this variant. The assay documentation lists calibrated assay methods, controls, and thresholds, but supplies no result for this variant; therefore PS3 cannot be evaluated without variant-specific assay data.
VCEP rule
Calibrated functional assays with functional odds for Pathogenicity > 18.7 OR calibrated functional assays with functional odds for pathogenicity >4.3 and <= 18.7 OR MMR function defect following functional assay flowchart OR variants with monoallelic expression: complete loss of expression (<10% of wild-type in cDNA without puromycin) of the variant allele.
Evidence considered
ClinGen InSiGHT PMS2 VCEP v2.0 PS3 rule: calibrated functional assays support PS3 at calibrated functional odds >18.7 (Strong), >4.3 and <=18.7 (Moderate), or >2.08 and <=4.3 (Supporting); no variant-specific functional odds are provided.
Functional-assay-SVI-documentation-MMR.xlsx, sheet MMR assays: approved calibrated assays are documented with controls and readout thresholds, including the PMS2 abnormal-readout threshold <18% for the applicable CIMRA assay, but the table contains no row for c.73C>T, p.Gln25Ter, or p.Q25*.
Functional-assay-flowchart.pdf: the converted file contains no variant-specific entry for c.73C>T, p.Gln25Ter, or p.Q25*; no assay result can be classified through the flowchart.
Still missing
Functional-assay-SVI-documentation-MMR.xlsx: no entry found for c.73C>T, p.Gln25Ter, or p.Q25*.
Functional-assay-flowchart.pdf: no entry found for c.73C>T, p.Gln25Ter, or p.Q25*.
No variant-specific PMS2 functional assay readout, calibrated functional odds, or qualifying MMR function-defect result is available.
PM3VCEPNot assessed: no affected-proband observation, pathogenic PMS2 allele, or confirmed trans/cis phase is documented to generate a PM3 point total.
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Reasoning
The PMS2 VCEP assigns PM3 strength from a point total: Very Strong for ≥4 points, Strong for 2–3.5 points, Moderate for 1–1.5 points, and Supporting for = 0.5 points. The available case evidence does not document an affected proband carrying NM_000535.7:c.73C>T together with a pathogenic PMS2 variant, a confirmed trans or cis phase relationship, or any other PM3 point-bearing observation. A different PMS2 compound-variant case in PMID:16144131 cannot be transferred to this variant because c.73C>T is not mentioned. Therefore no PM3 point total can be established.
ClinGen InSiGHT PMS2 CSPEC PM3 rule: the criterion is strength-graded by PM3 point totals of ≥4, 2–3.5, 1–1.5, or =0.5 points.
No case-level record documents NM_000535.7:c.73C>T in an affected proband with a second pathogenic PMS2 variant or confirmed phase.
Two constitutional PMS2 variants were reported in a different Turcot syndrome family, 1951C>T (p.Gln643Ter) and 161G>T (p.Ser46Ile), on different alleles; the paper does not mention c.73C>T or p.(Gln25Ter), so it cannot provide PM3 evidence for this variant.
Still missing
Affected-proband observations involving NM_000535.7:c.73C>T are not documented.
A second pathogenic or likely pathogenic PMS2 variant and its phase relative to c.73C>T are not documented.
Inheritance or parental/offspring testing sufficient to establish phase is not documented.
PP1VCEPNot assessed: no variant-specific pedigree, relative genotypes, meioses, or combined Bayes Likelihood Ratio is available for PP1.
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Reasoning
The VCEP requires a combined Bayes Likelihood Ratio from disease co-segregation to assign PP1, but no pedigree, affected or unaffected relative genotypes, meioses, family count, or calculated Bayes Likelihood Ratio is available for NM_000535.7:c.73C>T. The variant-specific literature extracts likewise provide no segregation dataset for this variant.
VCEP rule
Strong: combined Bayes Likelihood Ratio >18.7 in ≥2 families; Moderate: >4.3 and ≤18.7; Supporting: >2.08 and ≤4.3
Evidence considered
No variant-specific co-segregation analysis, pedigree, relative genotype set, informative meiosis count, or combined Bayes Likelihood Ratio is present in the case evidence.
The reviewed variant-specific literature extracts do not mention NM_000535.7:c.73C>T or p.(Gln25Ter) and do not provide segregation evidence for it.
PP4VCEPNot assessed: no patient-specific MSI, tumor-genome, or PMS2 IHC result is available to compare with the VCEP PP4 tumor-evidence rule.
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Reasoning
The VCEP PP4 rule requires CRC/endometrial MSI-H tumor evidence and/or MMR-protein loss consistent with the variant location, with strength based on the number of independent tumors. The available case evidence does not provide patient-specific MSI, tumor-genome, or PMS2 IHC findings for NM_000535.7:c.73C>T. The governing Table-for-CMMRD-diagnosis.pdf was searched for c.73C>T, p.Gln25Ter, and p.Q25* and contained no variant entry; VCEP-pilot-variants---MMR.xlsx was searched for the same notations and contained no variant entry. Therefore PP4 cannot be assessed.
Evidence considered
The VCEP PP4 Supporting rule requires "1 CRC/Endometrial MSI-H tumor using a standard panel of 5-10 markers or tumor genome and/or loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4."
The case bundle contains no patient-specific MSI, tumor-genome, or PMS2 IHC result for NM_000535.7:c.73C>T (p.Gln25Ter; p.Q25*).
Table-for-CMMRD-diagnosis.pdf was searched in full for c.73C>T, p.Gln25Ter, and p.Q25*; no entry for this variant was found.
VCEP-pilot-variants---MMR.xlsx was searched in full for c.73C>T, p.Gln25Ter, and p.Q25*; no entry for this variant was found.
Still missing
Patient-specific CRC or endometrial MSI-H tumor result using the VCEP standard marker panel or tumor genome is unavailable.
Patient-specific MMR immunohistochemistry result showing PMS2 loss consistent with the variant location is unavailable.
No entry for c.73C>T, p.Gln25Ter, or p.Q25* was found in Table-for-CMMRD-diagnosis.pdf searched at /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PMS2/fulltext/Table-for-CMMRD-diagnosis.pdf.txt.
No entry for c.73C>T, p.Gln25Ter, or p.Q25* was found in VCEP-pilot-variants---MMR.xlsx searched at /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PMS2/fulltext/VCEP-pilot-variants---MMR.xlsx.txt.
BA1VCEPNot assessed: gnomAD v4 total AF is 6.20819e-07, but the VCEP requires a Grpmax filtering AF, which is unavailable.
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Reasoning
The InSiGHT PMS2 VCEP requires a gnomAD v4 Grpmax filtering allele frequency of at least 0.0028 (0.28%) and exclusion of a founder pathogenic variant. The available gnomAD v4 record reports total AF 6.208187854797936e-07 (1/1610776 alleles), highest listed subpopulation AF 8.476041620754774e-07, and zero homozygotes, but the required Grpmax filtering AF is null. Therefore the VCEP BA1 threshold cannot be directly evaluated from the available data; no BA1 pre-assignment was found for this variant in the searched pilot table.
VCEP rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.0028 (0.28%) and variant is excluded as founder pathogenic variant.
Evidence considered
InSiGHT PMS2 VCEP CSPEC BA1 rule: gnomAD v4 Grpmax filtering AF must be >=0.0028 (0.28%) and the variant must be excluded as a founder pathogenic variant.
gnomAD v4.1 record for NM_000535.7:c.73C>T (p.Gln25Ter/p.Q25*): total AF 6.208187854797936e-07, 1/1610776 alleles, homozygotes 0; highest listed subpopulation AF 8.476041620754774e-07; grpmax_faf null.
Still missing
The required gnomAD v4 Grpmax filtering allele frequency is unavailable (reported as null).
Founder-pathogenic-variant exclusion is not documented in the available evidence.
BS1VCEPNot assessed: gnomAD v4 total AF is 6.20819e-07, but the VCEP requires a Grpmax filtering AF, which is unavailable.
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Reasoning
The InSiGHT PMS2 VCEP requires a gnomAD v4 Grpmax filtering allele frequency of at least 0.00028 and less than 0.0028, with exclusion of a founder pathogenic variant. The available gnomAD v4 record reports total AF 6.208187854797936e-07 and highest listed subpopulation AF 8.476041620754774e-07, but the required Grpmax filtering AF is null. Therefore the VCEP BS1 threshold cannot be directly evaluated from the available data.
VCEP rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.00028 and \< 0.0028 (0.028-0.28%) and variant is excluded as founder pathogenic variant.
Evidence considered
InSiGHT PMS2 VCEP CSPEC BS1 rule: gnomAD v4 Grpmax filtering AF must be >=0.00028 and <0.0028 (0.028-0.28%), and the variant must be excluded as a founder pathogenic variant.
gnomAD v4.1 record for NM_000535.7:c.73C>T (p.Gln25Ter/p.Q25*): total AF 6.208187854797936e-07, 1/1610776 alleles, homozygotes 0; highest listed subpopulation AF 8.476041620754774e-07; grpmax_faf null.
Still missing
The required gnomAD v4 Grpmax filtering allele frequency is unavailable (reported as null).
Founder-pathogenic-variant exclusion is not documented in the available evidence.
BS2VCEPNot assessed: no qualifying in-trans co-occurrence, cancer-age, CMMRD-exclusion, or phase-confirmation evidence is available.
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Reasoning
The VCEP BS2 rule requires documented in-trans co-occurrence with a known pathogenic variant in PMS2 in a patient meeting the specified cancer-age condition, absence of CMMRD manifestations, and phase confirmation through parental or offspring testing. The available case evidence contains no qualifying co-occurrence, clinical-age, CMMRD-exclusion, or phase-confirmation record.
VCEP rule
Co-occurrence _in trans_ with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 (or other LS cancer above the median age of onset for that cancer in LS<sup>d</sup>), and who has no previous or current evidence of clinical manifestations of CMMRD as per Aronson et al 2022 (Refer to 'Table for CMMRD diagnosis.pdf'). Confirmation of phase requires testing of parents or offspring.
Evidence considered
InSiGHT PMS2 VCEP CSPEC BS2 rule requires in-trans co-occurrence with a known pathogenic variant in the same gene, the specified cancer-age context, no clinical manifestations of CMMRD, and phase confirmation by testing parents or offspring.
No qualifying BS2 case-level evidence was identified in the available case materials.
Still missing
No qualifying in-trans co-occurrence with a known pathogenic PMS2 variant is documented.
No required cancer age, CMMRD-exclusion, or parental/offspring phase-confirmation data are available.
BS3VCEPNot assessed: no variant-specific proficient-function result or calibrated functional odds are available for comparison with the VCEP BS3 thresholds.
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Reasoning
The governing PMS2 VCEP permits BS3 from calibrated functional assays with functional odds for pathogenicity <=0.05 or >0.05 and <=0.48, or from variant-specific proficient function in protein and mRNA-based laboratory assays following the VCEP functional-assay flowchart. The case contains no variant-specific functional result for NM_000535.7:c.73C>T (NP_000526.2:p.(Gln25Ter), p.(Q25*)). Exact searches for c.73C>T, p.Gln25Ter, and p.Q25* in Functional-assay-SVI-documentation-MMR.xlsx.txt and Functional-assay-flowchart.pdf.txt found no entry for this variant. The assay documentation lists calibrated assay methods, controls, and thresholds, but supplies no result for this variant; therefore BS3 cannot be evaluated without variant-specific assay data.
VCEP rule
Calibrated functional assays with functional odds for Pathogenicity <= 0.05 OR calibrated functional assays with functional odds for Pathogenicity >0.05 and <=0.48 OR variant-specific proficient function in protein and mRNA-based lab assays as per MMR functional assay flowchart.
Evidence considered
ClinGen InSiGHT PMS2 VCEP v2.0 BS3 rule: calibrated functional assays support BS3 at functional odds for pathogenicity <=0.05 (Strong) or >0.05 and <=0.48 (Supporting), or with variant-specific proficient function in protein and mRNA-based assays per the MMR functional assay flowchart; no such variant-specific result is provided.
Functional-assay-SVI-documentation-MMR.xlsx, sheet MMR assays: approved calibrated assays are documented with controls and readout thresholds, but the table contains no row for c.73C>T, p.Gln25Ter, or p.Q25*.
Functional-assay-flowchart.pdf: the converted file contains no variant-specific entry for c.73C>T, p.Gln25Ter, or p.Q25*; no assay result can be classified through the flowchart.
Still missing
Functional-assay-SVI-documentation-MMR.xlsx: no entry found for c.73C>T, p.Gln25Ter, or p.Q25*.
Functional-assay-flowchart.pdf: no entry found for c.73C>T, p.Gln25Ter, or p.Q25*.
No variant-specific PMS2 protein or mRNA proficient-function result, calibrated functional odds, or qualifying benign functional result is available.
BS4VCEPNot assessed: no variant-specific non-segregation pedigree, relative data, meioses, or combined Bayes Likelihood Ratio is available for BS4.
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Reasoning
The VCEP requires a combined Bayes Likelihood Ratio from lack of disease co-segregation to assign BS4, but no pedigree, non-segregating relatives, phenotype assessment, meioses, or calculated Bayes Likelihood Ratio is available for NM_000535.7:c.73C>T. The variant-specific literature extracts do not provide non-segregation evidence for this variant.
VCEP rule
Strong: combined Bayes Likelihood Ratio <0.05; Supporting: >0.05 and ≤0.48
Evidence considered
No variant-specific lack-of-co-segregation analysis, pedigree, non-segregating relative data, informative meiosis count, or combined Bayes Likelihood Ratio is present in the case evidence.
The reviewed variant-specific literature extracts do not mention NM_000535.7:c.73C>T or p.(Gln25Ter) and do not provide non-segregation evidence for it.
Still missing
Variant-specific pedigree and phenotype data
Genotypes and disease status of non-segregating relatives
BP5VCEPNot assessed: no patient-specific MSS, MMR-protein, BRAF V600E, or MLH1-methylation tumor evidence is available for the BP5 alternate-basis rule.
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Reasoning
BP5 is applicable under the PMS2 VCEP, but the case evidence does not document the required alternate-basis tumor findings: at least 2 or 3 qualifying tumors for supporting evidence, at least 4 for strong evidence, or the specified BRAF V600E/MLH1-methylation findings. No patient-specific tumor MSS, MMR-protein, BRAF V600E, or MLH1 methylation result is available. The VCEP reference files Table-for-CMMRD-diagnosis.pdf and VCEP-pilot-variants---MMR.xlsx were searched for c.73C>T, p.Gln25Ter, and p.Q25* and contained no variant entry. Therefore BP5 cannot be assessed.
Evidence considered
The VCEP BP5 Supporting rule requires "2 or 3 tumors: CRC/Endometrial tumors with MSS and/or no loss of MMR protein expression and/or LS spectrum tumors with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation", or one specified BRAF V600E/MLH1-methylation finding.
The case evidence provides no patient-specific tumor MSS, MMR-protein, BRAF V600E, or MLH1 methylation result for NM_000535.7:c.73C>T.
Table-for-CMMRD-diagnosis.pdf was searched in full for c.73C>T, p.Gln25Ter, and p.Q25*; no entry for this variant was found.
VCEP-pilot-variants---MMR.xlsx was searched in full for c.73C>T, p.Gln25Ter, and p.Q25*; no entry for this variant was found.
Still missing
Patient-specific tumor MSS status and MMR-protein expression results are unavailable.
Patient-specific BRAF V600E or MLH1 methylation results are unavailable.
No entry for c.73C>T, p.Gln25Ter, or p.Q25* was found in Table-for-CMMRD-diagnosis.pdf searched at /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PMS2/fulltext/Table-for-CMMRD-diagnosis.pdf.txt.
No entry for c.73C>T, p.Gln25Ter, or p.Q25* was found in VCEP-pilot-variants---MMR.xlsx searched at /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PMS2/fulltext/VCEP-pilot-variants---MMR.xlsx.txt.
Not applicable · 15· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: the VCEP limits PS1 to predicted missense or specified non-canonical splice variants, whereas NM_000535.7:c.73C>T is a nonsense change, p.(Gln25Ter).
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Reasoning
The VCEP PS1 rule applies to a predicted missense substitution encoding the same amino acid change through a different nucleotide change, or to a non-canonical splice nucleotide; this variant is a nonsense change, NM_000535.7:c.73C>T, p.(Gln25Ter).
VCEP rule
A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic (not a predicted or confirmed splice defect).
Evidence considered
Case normalization identifies NM_000535.7:c.73C>T as NP_000526.2:p.(Gln25Ter), a nonsense variant; the VCEP PS1 rule is restricted to predicted missense substitutions or specified non-canonical splice variants.
PS4VCEPNot applicable: the PMS2 VCEP does not use PS4 proband counting because tumor IHC data are available for PP4 classification.
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Reasoning
The PMS2 VCEP explicitly marks PS4 as not applicable and states that PS4 is not used for MMR variant classification because tumor IHC data are available for classification through PP4. No PS4 proband-counting assessment is therefore performed.
VCEP rule
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.
Evidence considered
The VCEP CSPEC entry for PS4 states: "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."
PM1VCEPNot applicable: the PMS2 VCEP explicitly marks PM1 Not Applicable, and its domain-table material contains no authoritative PMS2 domain entry for residue 25.
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Reasoning
The PMS2 VCEP CSPEC marks PM1 as Not Applicable. The governing MMR-Functional-domains.pdf text was searched for c.73C>T, p.Gln25Ter, and p.Q25*; it contains only a schematic description and no variant-specific domain entry. vcep_materials.json has no domain_tables entry for PMS2.
VCEP rule
Not Applicable
Evidence considered
The PMS2 CSPEC applicability entry for PM1 is Not Applicable.
MMR-Functional-domains.pdf.txt was searched for c.73C>T, p.Gln25Ter, and p.Q25*; no variant-specific row or residue boundary was present.
vcep_materials.json domain_tables is empty for PMS2, so there is no authoritative domain-table entry to evaluate.
Still missing
MMR-Functional-domains.pdf.txt: no c.73C>T, p.Gln25Ter, or p.Q25* entry; the converted text contains only a schematic description.
PM5N/ANot applicable: the VCEP restricts PM5 to missense changes at the same residue, whereas p.(Gln25Ter) is a nonsense variant.
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Reasoning
The VCEP PM5 rule applies to a missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic or Likely Pathogenic on the protein level and not due to aberrant splicing; this variant is nonsense, p.(Gln25Ter), not missense.
VCEP rule
Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level and not due to aberrant splicing. Only use PM5 if PP3 is supporting for the missense change. Use PM5_Supporting if other variant is Likely Pathogenic due to a missense alteration.
Evidence considered
Case normalization identifies NM_000535.7:c.73C>T as NP_000526.2:p.(Gln25Ter), a nonsense variant; therefore the VCEP missense-only PM5 rule does not apply.
PP3N/ANot applicable: PP3 covers missense or non-canonical splice variants, whereas c.73C>T is a nonsense variant producing p.Gln25Ter.
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Reasoning
The VCEP PP3 rule is limited to missense variants evaluated by the HCI MAPP/PP2 Prior P score, or non-canonical splice nucleotides evaluated by SpliceAI. This variant is a nonsense variant, NM_000535.7:c.73C>T (p.Gln25Ter/p.Q25*), so PP3 is outside its governing scope. The governing HCI table was searched for c.73C>T, p.Gln25Ter, p.Q25*, and Q25; it contains other codon-25 substitutions but no exact entry for this variant. The available SpliceAI max delta score of 0.345 is therefore not used for PP3 because the VCEP splice path is restricted to non-canonical splice nucleotides and this variant is nonsense.
VCEP rule
Missense variant with “MAPP/PP2 Prior P” score >0.81 from [http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique](http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique)
OR
Missense variant with “MAPP/PP2 Prior P” score >0.68 & ≤0.81 from [http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique](http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique)
OR
Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.
Evidence considered
Variant consequence from the case evidence: NM_000535.7:c.73C>T is a nonsense variant encoding NP_000526.2:p.(Gln25Ter), also p.(Q25*).
VCEP PP3 scope: missense variants use the HCI MAPP/PP2 Prior P score; the alternative splice path is for predicted splice defects at non-canonical splicing nucleotides using SpliceAI.
SpliceAI case result: max delta score 0.345, not used because this nonsense variant is outside the VCEP PP3 splice-path scope.
Searched HCI-PRIORS-PMS2.txt.txt for c.73C>T, p.Gln25Ter, p.Q25*, and Q25; exact variant entry absent, while c.73C>A/p.Q25K, c.73C>G/p.Q25E, and other codon-25 substitutions were present.
Still missing
No exact c.73C>T, p.Gln25Ter, or p.Q25* entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PMS2/fulltext/HCI-PRIORS-PMS2.txt.txt; other codon-25 substitutions were present.
PP5VCEPNot applicable: the PMS2 VCEP explicitly prohibits use of PP5, regardless of ClinVar pathogenic reports.
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Reasoning
The PMS2 VCEP marks PP5 as not applicable for this VCEP and explicitly states that the criterion is not for use. ClinVar's pathogenic submissions and associated literature therefore cannot be converted into PP5 evidence under this governing framework.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
The VCEP CSPEC entry for PP5 states: "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee."
ClinVar reports the variant as pathogenic, but that report is not usable as PP5 because the governing VCEP marks PP5 not applicable.
BP4N/ANot applicable: BP4 covers missense, intronic, or synonymous variants, whereas c.73C>T is a nonsense variant producing p.Gln25Ter.
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Reasoning
The VCEP BP4 rule applies to missense variants with an HCI MAPP/PP2 Prior P score below 0.11, or to intronic and synonymous variants for which SpliceAI predicts no splicing impact with delta score ≤0.1. This variant is a nonsense variant, NM_000535.7:c.73C>T (p.Gln25Ter/p.Q25*), so BP4 is outside its governing scope. A no-splice-impact result cannot negate the truncating protein consequence. The governing HCI table was searched for c.73C>T, p.Gln25Ter, p.Q25*, and Q25; it contains other codon-25 substitutions but no exact entry for this variant.
VCEP rule
Missense variant with “MAPP/PP2 Prior P” score <0.11 from [http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique](http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique)
OR
For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.
Evidence considered
Variant consequence from the case evidence: NM_000535.7:c.73C>T is a nonsense variant encoding NP_000526.2:p.(Gln25Ter), also p.(Q25*).
VCEP BP4 scope: missense variants use the HCI MAPP/PP2 Prior P score below 0.11; intronic and synonymous variants use SpliceAI no-impact delta score ≤0.1.
SpliceAI case result: max delta score 0.345; it is not used to apply BP4 because the variant is neither missense, intronic, nor synonymous.
Searched HCI-PRIORS-PMS2.txt.txt for c.73C>T, p.Gln25Ter, p.Q25*, and Q25; exact variant entry absent, while other codon-25 substitutions were present.
Still missing
No exact c.73C>T, p.Gln25Ter, or p.Q25* entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PMS2/fulltext/HCI-PRIORS-PMS2.txt.txt; other codon-25 substitutions were present.
BP6VCEPNot applicable: the PMS2 VCEP explicitly prohibits use of BP6 for this gene-specific interpretation.
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Reasoning
The PMS2 VCEP marks BP6 as not applicable for this VCEP and explicitly states that the criterion is not for use. No reputable-source benign report can therefore be applied as BP6 under this governing framework.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
The VCEP CSPEC entry for BP6 states: "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee."
BP7N/ANot applicable: BP7 covers synonymous or intronic variants, whereas c.73C>T is a nonsense variant producing p.Gln25Ter.
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Reasoning
The VCEP BP7 rule is limited to synonymous (silent) or intronic variants at or beyond -21/+7 of the exonic boundaries. This variant is a coding nonsense variant, NM_000535.7:c.73C>T (p.Gln25Ter/p.Q25*), not a synonymous or intronic variant, so BP7 is not applicable.
VCEP rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.
Evidence considered
Variant consequence from the case evidence: NM_000535.7:c.73C>T is a nonsense variant encoding NP_000526.2:p.(Gln25Ter), also p.(Q25*).
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.20819e-07; MAF= 0.00006%, 1/1610776 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47604e-07; MAF= 0.00008%, 1/1179796 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat +44 bp
0.345
SpliceAI acceptor gainat -18 bp
0.003
SpliceAI donor lossat -90 bp
0.216
SpliceAI donor gainat +339 bp
0.033
Pangolin splice lossmagnitude shown
-0.556
Pangolin splice gain
0.012
Other predictors
REVEL
Not available
BayesDel
0.656
How the predictions were used
PP3N/ANot applicable: PP3 covers missense or non-canonical splice variants, whereas c.73C>T is a nonsense variant producing p.Gln25Ter.
Details ▾Hide ▴
Reasoning
The VCEP PP3 rule is limited to missense variants evaluated by the HCI MAPP/PP2 Prior P score, or non-canonical splice nucleotides evaluated by SpliceAI. This variant is a nonsense variant, NM_000535.7:c.73C>T (p.Gln25Ter/p.Q25*), so PP3 is outside its governing scope. The governing HCI table was searched for c.73C>T, p.Gln25Ter, p.Q25*, and Q25; it contains other codon-25 substitutions but no exact entry for this variant. The available SpliceAI max delta score of 0.345 is therefore not used for PP3 because the VCEP splice path is restricted to non-canonical splice nucleotides and this variant is nonsense.
VCEP rule
Missense variant with “MAPP/PP2 Prior P” score >0.81 from [http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique](http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique)
OR
Missense variant with “MAPP/PP2 Prior P” score >0.68 & ≤0.81 from [http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique](http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique)
OR
Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.
Evidence considered
Variant consequence from the case evidence: NM_000535.7:c.73C>T is a nonsense variant encoding NP_000526.2:p.(Gln25Ter), also p.(Q25*).
VCEP PP3 scope: missense variants use the HCI MAPP/PP2 Prior P score; the alternative splice path is for predicted splice defects at non-canonical splicing nucleotides using SpliceAI.
SpliceAI case result: max delta score 0.345, not used because this nonsense variant is outside the VCEP PP3 splice-path scope.
Searched HCI-PRIORS-PMS2.txt.txt for c.73C>T, p.Gln25Ter, p.Q25*, and Q25; exact variant entry absent, while c.73C>A/p.Q25K, c.73C>G/p.Q25E, and other codon-25 substitutions were present.
Still missing
No exact c.73C>T, p.Gln25Ter, or p.Q25* entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PMS2/fulltext/HCI-PRIORS-PMS2.txt.txt; other codon-25 substitutions were present.
BP4N/ANot applicable: BP4 covers missense, intronic, or synonymous variants, whereas c.73C>T is a nonsense variant producing p.Gln25Ter.
Details ▾Hide ▴
Reasoning
The VCEP BP4 rule applies to missense variants with an HCI MAPP/PP2 Prior P score below 0.11, or to intronic and synonymous variants for which SpliceAI predicts no splicing impact with delta score ≤0.1. This variant is a nonsense variant, NM_000535.7:c.73C>T (p.Gln25Ter/p.Q25*), so BP4 is outside its governing scope. A no-splice-impact result cannot negate the truncating protein consequence. The governing HCI table was searched for c.73C>T, p.Gln25Ter, p.Q25*, and Q25; it contains other codon-25 substitutions but no exact entry for this variant.
VCEP rule
Missense variant with “MAPP/PP2 Prior P” score <0.11 from [http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique](http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique)
OR
For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.
Evidence considered
Variant consequence from the case evidence: NM_000535.7:c.73C>T is a nonsense variant encoding NP_000526.2:p.(Gln25Ter), also p.(Q25*).
VCEP BP4 scope: missense variants use the HCI MAPP/PP2 Prior P score below 0.11; intronic and synonymous variants use SpliceAI no-impact delta score ≤0.1.
SpliceAI case result: max delta score 0.345; it is not used to apply BP4 because the variant is neither missense, intronic, nor synonymous.
Searched HCI-PRIORS-PMS2.txt.txt for c.73C>T, p.Gln25Ter, p.Q25*, and Q25; exact variant entry absent, while other codon-25 substitutions were present.
Still missing
No exact c.73C>T, p.Gln25Ter, or p.Q25* entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PMS2/fulltext/HCI-PRIORS-PMS2.txt.txt; other codon-25 substitutions were present.
BP7N/ANot applicable: BP7 covers synonymous or intronic variants, whereas c.73C>T is a nonsense variant producing p.Gln25Ter.
Details ▾Hide ▴
Reasoning
The VCEP BP7 rule is limited to synonymous (silent) or intronic variants at or beyond -21/+7 of the exonic boundaries. This variant is a coding nonsense variant, NM_000535.7:c.73C>T (p.Gln25Ter/p.Q25*), not a synonymous or intronic variant, so BP7 is not applicable.
VCEP rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.
Evidence considered
Variant consequence from the case evidence: NM_000535.7:c.73C>T is a nonsense variant encoding NP_000526.2:p.(Gln25Ter), also p.(Q25*).
SpliceAI predicts possible splice impact for this variant (max delta score = 0.34). BayesDel score = 0.655873.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
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.
Two PMS2 mutations in a Turcot syndrome family with small bowel cancers.
This paper reports a different PMS2 nonsense variant, Q643X, and a missense variant, S46I, in a Turcot syndrome family with early-onset duodenal cancer, glioblastoma, and adenomas; tumors and normal cells showed absent PMS2 expression and increased microsatellite instability. It does not mention c.73C>T or p.(Q25*), so it does not provide variant-specific PP4 or BP5 evidence.
two constitutional PMS2 mutations were identified: a truncating nonsense mutation in exon 11 (1951C>T; Q643X) and a missense mutation affecting exon 2 (161G>T; S46I)
Results, PMS2 mutation analysis; Discussion
MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer.
This observational study describes seven participants in six PMS2 mutation-positive families, including colorectal, renal, and small-intestine cancers, and reports an attenuated PMS2 phenotype with older onset. It does not mention c.73C>T or p.(Q25*), so it does not provide variant-specific PP4 or BP5 evidence.
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.
PMS2 monoallelic mutation carriers: the known unknown.
Goodenberger ML et al. · 2016
This paper reviews 234 monoallelic PMS2 mutation carriers from 170 families, including 159 individuals with colorectal cancer; among cases with known tumor immunohistochemistry, nearly all showed isolated PMS2 loss, and among cases with known microsatellite status, 50 of 51 were MSI-high. It does not explicitly mention PMS2 c.73C>T or p.(Q25*), so these are gene-level observations and cannot establish PP4 or BP5 for this variant.
Table S1, Table S2, and Table S3 show details regarding the 234 monoallelic PMS2 mutation carriers from 170 families that were included in the final dataset
Results, paragraph 1; Results, paragraphs 4-5
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.11 / 1,610,776 recorded allelesOpen source ↗
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.20819e-07; MAF= 0.00006%, 1/1610776 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47604e-07; MAF= 0.00008%, 1/1179796 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (2 clinical laboratories). (ClinVarID = 492293)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.34). BayesDel score = 0.655873.
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; COSV56151812, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 11.0.06.
The current version is 11.0.07.
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