The PMS2 NM_000535.7:c.903+4T>A (NP_000526.2:p.?) intronic variant has not previously been reported in somatic cancers (COSMIC). 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.
Words with a dotted underline have a short definition. Hover or tap them.
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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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.
Met: SpliceAI maximum delta score 0.209 meets the VCEP threshold of >=0.2 for a non-canonical splice variant.
Benign criteria applied · 1
BS1Strong
BS1 · strong
Met, Strong: gnomAD v4.1 Grpmax filtering allele frequency is 0.00072347, within the VCEP's 0.00028 to <0.0028 BS1 interval.
Recorded classification: Uncertain significance
VUS: BS1 (strong) provides benign evidence, while PP3 (supporting) provides pathogenic evidence; neither side satisfies a complete VCEP classification rule.
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
98 / 1,606,818 alleles
gnomAD v4.1: 98 / 1,606,818 alleles. Recorded AF 6.09901e-05. Recorded homozygote count 2.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000116811; MAF= 0.01168%, 33/282508 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00101327; MAF= 0.10133%, 31/30594 alleles, homozygotes = 0); grpmax FAF= 0.00073312.
ACMG/AMP criteria under ClinGen PMS2 VCEP v2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 3 not met · 10 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For the requested consequence/LOF criteria, the PMS2 VCEP marks PM4 and BP3 not applicable, while its PVS1 rule does not cover this non-canonical +4 intronic variant without qualifying RNA evidence.
The required VCEP decision-tree and pilot-variant files were searched for c.903+4T>A and p.?; neither contains a matching pre-assigned row.
Applied only the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel PMS2 Version 2.0 PS3 and BS3 rules.
Both on-record VCEP functional files were searched for c.903+4T>A and p.?; neither contains a variant-specific entry.
The available case evidence contains no calibrated functional odds or variant-specific RNA, protein, or concordant assay result that satisfies either criterion.
PS3 and BS3 are therefore not_assessed rather than not_met or not_applicable.
Within the requested criterion group, PS4, PP5, and BP6 are not applicable under the PMS2 VCEP. PP4 and BP5 remain not assessed because the required patient-specific tumor or phenotype evidence is unavailable.
Population evidence supports BS1 at Strong strength because the gnomAD v4.1 Grpmax filtering allele frequency is 0.00072347, within the VCEP's BS1 interval.
BA1 and PM2 are not met because the gnomAD v4.1 frequency is below the BA1 threshold but above the PM2 threshold.
BS2 is not assessed because the required in-trans co-occurrence, clinical, CMMRD, and phase evidence is unavailable.
No criteria match.
Met · 2
PP3SupportingVCEPMet: SpliceAI maximum delta score 0.209 meets the VCEP threshold of >=0.2 for a non-canonical splice variant.
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Reasoning
The variant is intronic at c.903+4T>A, a non-canonical splice position. The PMS2 VCEP permits PP3 Supporting for a predicted splice defect at a non-canonical splicing nucleotide when SpliceAI delta score is >= 0.2. The available SpliceAI result has DS_AG 0.209 and DS_DG 0.138, with maximum delta score 0.209; therefore the named predictor and cutoff are satisfied. The HCI missense-prior path is outside scope for this intronic variant, and a search of HCI-PRIORS-PMS2.txt.txt found no exact c.903+4T>A or p.? entry, but the VCEP's separate splice-prediction path is met.
VCEP rule
Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.
Evidence considered
SpliceAI result for NM_000535.7:c.903+4T>A: DS_AG=0.209, DS_DG=0.138, maximum delta score=0.209.
The VCEP rule's named splice path applies to non-canonical splicing nucleotides and requires SpliceAI delta score >= 0.2; the observed maximum is 0.209.
HCI-PRIORS-PMS2.txt.txt was searched for c.903+4T>A, c.903, and p.?; no exact variant entry was found.
Still missing
HCI-PRIORS-PMS2.txt.txt was searched for c.903+4T>A, c.903, and p.?; no exact entry was found. This missense-only lookup is not needed for the met intronic SpliceAI path.
BS1StrongVCEPMet, Strong: gnomAD v4.1 Grpmax filtering allele frequency is 0.00072347, within the VCEP's 0.00028 to <0.0028 BS1 interval.
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Reasoning
BS1 is met at Strong strength. The InSiGHT PMS2 VCEP requires a gnomAD v4 Grpmax filtering allele frequency of at least 0.00028 and less than 0.0028 (0.028-0.28%) and exclusion as a founder pathogenic variant. The variant's gnomAD v4.1 Grpmax filtering allele frequency is 0.00072347 (0.072347%), within that interval; the available record does not identify it as a founder pathogenic variant.
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 allele frequency >= 0.00028 and < 0.0028 (0.028-0.28%) and variant is excluded as founder pathogenic variant.
gnomAD v4.1: variant NM_000535.7:c.903+4T>A has Grpmax filtering allele frequency 0.00072347 (0.072347%); no founder pathogenic designation is reported in the available record.
Still missing
VCEP-pilot-variants---MMR.xlsx was searched for c.903+4T>A, p.?, and 903+4; no matching entry was found.
PM2VCEPNot met: gnomAD v4.1 total allele frequency is 0.0000609901, above the VCEP's <0.00002 PM2 threshold.
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Reasoning
PM2 is not met. The InSiGHT PMS2 VCEP requires an allele frequency below 0.00002 in the gnomAD v4 dataset. The gnomAD v4.1 all-comers total allele frequency is 0.0000609901 (98/1606818 alleles), which is above 0.00002; the VCEP rule specifies gnomAD v4 and does not require the non-cancer subset.
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 gnomAD v4 dataset.
gnomAD v4.1 all-comers: variant NM_000535.7:c.903+4T>A has total AF 6.099010591118596e-05, 98/1606818 alleles, and 2 homozygotes.
The separately reported gnomAD v2.1 non-cancer exome AF is 0.000135175 (32/236730 alleles, 0 homozygotes), and gnomAD v3.1 non-cancer genome AF is 2.02747e-05 (3/147968 alleles, 0 homozygotes); neither changes the VCEP-specified gnomAD v4 result.
Still missing
VCEP-pilot-variants---MMR.xlsx was searched for c.903+4T>A, p.?, and 903+4; no matching entry was found.
BA1VCEPNot met: gnomAD v4.1 Grpmax filtering allele frequency is 0.00072347, below the VCEP's 0.0028 BA1 threshold.
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Reasoning
BA1 is not met. The InSiGHT PMS2 VCEP requires a gnomAD v4 Grpmax filtering allele frequency of at least 0.0028 (0.28%) and exclusion as a founder pathogenic variant. The variant's gnomAD v4.1 Grpmax filtering allele frequency is 0.00072347 (0.072347%), below 0.0028; the available record does not identify it as a founder pathogenic variant.
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 allele frequency >= 0.0028 (0.28%) and variant is excluded as founder pathogenic variant.
gnomAD v4.1: variant NM_000535.7:c.903+4T>A has total AF 6.09901e-05, 98/1606818 alleles, 2 homozygotes, and Grpmax filtering allele frequency 0.00072347; no founder pathogenic designation is reported in the available record.
Still missing
VCEP-pilot-variants---MMR.xlsx was searched for c.903+4T>A, p.?, and 903+4; no matching entry was found.
BP4VCEPNot met: SpliceAI maximum delta score 0.209 exceeds the VCEP no-impact threshold of <=0.1.
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Reasoning
The variant is intronic, so the VCEP's intronic/synonymous BP4 path is applicable. That path requires SpliceAI to predict no splicing impact with delta score <= 0.1. SpliceAI reports a maximum delta score of 0.209, including DS_AG 0.209 and DS_DG 0.138, so the no-impact cutoff is not satisfied. The HCI missense-prior path is outside scope for this intronic variant; a search of HCI-PRIORS-PMS2.txt.txt found no exact c.903+4T>A or p.? entry.
VCEP rule
For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.
Evidence considered
SpliceAI result for NM_000535.7:c.903+4T>A: DS_AG=0.209, DS_DG=0.138, maximum delta score=0.209.
The VCEP intronic/synonymous BP4 path requires SpliceAI delta score <= 0.1; the observed maximum score is 0.209.
HCI-PRIORS-PMS2.txt.txt was searched for c.903+4T>A, c.903, and p.?; no exact variant entry was found.
Still missing
HCI-PRIORS-PMS2.txt.txt was searched for c.903+4T>A, c.903, and p.?; no exact entry was found. The missense-prior path is outside scope for this intronic variant.
PS1VCEPNot assessed: SpliceAI max delta is 0.209, but no confirmed Pathogenic comparator at the same non-canonical splice nucleotide was found.
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Reasoning
The VCEP permits PS1 for a variant affecting the same non-canonical splice nucleotide as a confirmed Pathogenic splice variant when SpliceAI predicts similar or worse splicing. This variant is NM_000535.7:c.903+4T>A with NP_000526.2:p.? and SpliceAI max delta 0.209, but no confirmed Pathogenic comparator at c.903+4T>A was found in MMR-Functional-domains.pdf.txt; therefore the required comparator relationship cannot be evaluated and PS1 is not assigned.
VCEP rule
Variants affecting the same non-canonical splice nucleotide as a confirmed Pathogenic splice variant with similar or worse splicing in silico prediction using SpliceAI.
Evidence considered
The VCEP PS1 rule requires a variant affecting the same non-canonical splice nucleotide as a confirmed Pathogenic splice variant with similar or worse SpliceAI prediction.
Case evidence: NM_000535.7:c.903+4T>A; normalized protein consequence NP_000526.2:p.?; SpliceAI max delta score 0.209.
MMR-Functional-domains.pdf.txt was searched for c.903+4T>A, p.?, and p.?; no matching variant entry was found, so no confirmed Pathogenic comparator was available from that governing VCEP file.
Still missing
No entry for c.903+4T>A, p.?, or p.? was found in MMR-Functional-domains.pdf.txt; a confirmed Pathogenic comparator at the same non-canonical splice nucleotide remains unavailable.
PS2VCEPNot assessed: no documented de novo event, parental confirmation, Lynch-spectrum tumor testing, or assignable de novo points are available.
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Reasoning
The VCEP permits PS2 when a proband has a de novo PMS2 variant, with points determined by confirmation of maternity and paternity and by Lynch-spectrum tumor testing. The case evidence contains no documented de novo observation, parental testing, proband tumor MSI/IHC/methylation results, or de novo points; therefore the criterion cannot be evaluated.
VCEP rule
Proband with a _de novo_ variant with both maternity and paternity confirmed in a case with MMR deficient LS spectrum tumor\* (i.e. MSI/IHC consistent with affected gene, with no MLH1 methylation in tumor tissue, with the exception of MLH1 constitutional promoter methylation). Refer to Appendix for protein expression consistent with variant location. **2 points per proband**
OR
Proband with a _de novo_ variant with both maternity and paternity confirmed in a case with LS spectrum tumor\* (with no tumor data for MSI/IHC/methylation). **1 point per proband**
OR
Proband with assumed _de novo_ variant and maternity and/or paternity unconfirmed with LS spectrum tumor\* (No tumor data for MSI/IHC/methylation). **0.5 points per proband**
\*Lynch Syndrome (LS) tumors include: colorectal/colon/rectal, endometrial, ovarian, small bowel/small intestine, renal pelvis, ureter, and stomach/gastric carcinomas, sebaceous skin tumors (adenomas and carcinomas), gliomas.
Evidence considered
No proband-level de novo, parental-testing, tumor, pedigree, or de novo-point evidence was identified in the case evidence reviewed.
Still missing
Documented proband de novo status
Maternity and paternity confirmation
Lynch-spectrum tumor type and MSI/IHC/methylation results
Number of qualifying probands and total de novo points
PS3VCEPNot assessed: the two governing VCEP functional files contain no variant-specific assay result, functional odds, or RNA finding for c.903+4T>A.
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Reasoning
The ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP PMS2 specification v2.0 requires calibrated functional evidence, an MMR function defect evaluated through the MMR functional assay flowchart, or the specified monoallelic-expression result for PS3. The variant NM_000535.7:c.903+4T>A (NP_000526.2:p.?) was searched in Functional-assay-SVI-documentation-MMR.xlsx.txt and Functional-assay-flowchart.pdf.txt using c.903+4T>A and p.?; neither file contains a variant-specific entry. The case evidence also contains no variant-specific calibrated functional odds, assay readout, patient-derived RNA result, or two independent concordant functional assays. Therefore PS3 cannot be assessed; the absence of a matching VCEP-file entry is an evidence gap and is not evidence of a benign or damaging result.
Evidence considered
VCEP CSPEC PS3 rule: calibrated functional assays with functional odds for Pathogenicity > 18.7 support Strong; functional odds >4.3 and <=18.7, an MMR function defect following the functional assay flowchart, or complete loss of monoallelic expression <10% of wild-type support Moderate; functional odds >2.08 and <=4.3 support Supporting.
Functional-assay-SVI-documentation-MMR.xlsx, sheet 'MMR assays': lists validated MMR assays, controls, readout thresholds, and proposed PS3/BS3 strengths, but no row for c.903+4T>A or p.?.
Functional-assay-flowchart.pdf: for splice-site, silent, or intronic variants, directs evaluation through a splicing assay; complete impact requires patient-derived RNA evidence, while no impact requires NMD-inhibitor assays for proficient function; no variant-specific result is present for this variant.
The case evidence reports SpliceAI max delta 0.209, but this is an in-silico prediction and does not establish the VCEP-required functional assay result for PS3.
Still missing
No entry for c.903+4T>A or p.? was found in Functional-assay-SVI-documentation-MMR.xlsx.txt.
No entry for c.903+4T>A or p.? was found in Functional-assay-flowchart.pdf.txt.
No variant-specific calibrated functional odds, assay readout, patient-derived RNA result, or two independent concordant functional assays are available in the case evidence.
PM3VCEPNot assessed: no affected-proband, pathogenic-in-trans, phase, or inheritance observations are available to assign the VCEP's PM3 point total.
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Reasoning
The VCEP assigns PM3 strength from the total number of points contributed by affected individuals with the variant in trans with a pathogenic or likely pathogenic variant, but the available case evidence contains no affected-proband observations, second pathogenic allele, phase information, or inheritance data for NM_000535.7:c.903+4T>A. Therefore, no PM3 points can be assigned.
The case evidence contains no variant-specific affected-proband, pathogenic-in-trans, cis/trans phase, or inheritance observation for NM_000535.7:c.903+4T>A.
PP1VCEPNot assessed: no qualifying pedigree segregation data or combined Bayes Likelihood Ratio is available for comparison with the VCEP thresholds.
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Reasoning
The VCEP requires co-segregation in pedigrees and a combined Bayes Likelihood Ratio above a specified threshold for PP1 strength. The case evidence provides no qualifying affected or unaffected relatives, pedigree structure, meioses, segregation observations, or calculated combined Bayes Likelihood Ratio; therefore PP1 cannot be evaluated.
VCEP rule
Co-segregation with disease in pedigree(s) with a combined\* Bayes Likelihood Ratio >18.7 in ≥2 families.
OR
Co-segregation with disease in pedigree(s) with a combined\* Bayes Likelihood Ratio >4.3 & ≤18.7.
OR
Co-segregation with disease in pedigree(s) with a combined\* Bayes Likelihood Ratio >2.08 & ≤4.3.
Evidence considered
No pedigree, informative meiosis, co-segregation result, or combined Bayes Likelihood Ratio was identified in the case evidence reviewed.
Still missing
Pedigree with affected and unaffected tested relatives
Variant and phenotype status for each informative relative
PP4VCEPNot assessed: no qualifying MSI-H tumor, MMR-protein-loss result, or CMMRD phenotype is available to meet the PP4 rule.
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Reasoning
The VCEP requires one or more CRC/endometrial MSI-H tumors or qualifying loss of MMR protein expression, with higher strengths requiring specified numbers of independent tumors. The available case evidence contains no patient tumor MSI/IHC results or CMMRD clinical phenotype sufficient to evaluate PP4. The required VCEP reference files were searched for NM_000535.7:c.903+4T>A and protein notation NP_000526.2:p.?; no matching entry was found in Table-for-CMMRD-diagnosis.pdf or VCEP-pilot-variants---MMR.xlsx.
VCEP rule
1 CRC/Endometrial MSI-H tumor using a standard panel of 5-10 markers<sup>e</sup> 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.
Evidence considered
The PMS2 VCEP PP4 rule requires 1 CRC/endometrial MSI-H tumor or qualifying MMR-protein loss for Supporting, 2 independent tumors for Moderate, or at least 3 independent tumors in at least 2 families for Strong.
The case bundle provides no patient-specific MSI, MMR immunohistochemistry, or CMMRD phenotype findings for this variant.
Searched Table-for-CMMRD-diagnosis.pdf for c.903+4T>A, NP_000526.2:p.?, and p.?; no matching variant entry was found.
Searched VCEP-pilot-variants---MMR.xlsx for c.903+4T>A, NP_000526.2:p.?, and p.?; no matching variant entry was found.
Still missing
No patient-specific CRC/endometrial MSI-H tumor count or testing method is available.
No patient-specific MMR protein expression result is available.
No CMMRD clinical feature score is available; no matching variant entry was found in Table-for-CMMRD-diagnosis.pdf.
No matching variant entry was found in VCEP-pilot-variants---MMR.xlsx.
BS2VCEPNot assessed: no documented qualifying in-trans co-occurrence, cancer-age evidence, CMMRD assessment, or parental/offspring phase confirmation is available.
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Reasoning
BS2 cannot be assessed from the available case evidence. The VCEP requires documented co-occurrence in trans with a known pathogenic variant in PMS2, a qualifying cancer age or cancer type, absence of CMMRD manifestations, and phase confirmation through parental or offspring testing. No such co-occurrence, clinical, CMMRD, or phase-confirmation evidence is available in the reviewed case materials.
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 co-occurrence in trans with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 or another LS cancer above its median LS age of onset, no previous or current CMMRD manifestations, and phase confirmation by testing parents or offspring.
The case evidence contains no qualifying co-occurrence, phase, cancer-age, or CMMRD documentation for this variant.
Still missing
VCEP-pilot-variants---MMR.xlsx was searched for c.903+4T>A, p.?, and 903+4; no matching entry was found.
No qualifying in-trans co-occurrence report with a known pathogenic PMS2 variant, cancer-age information, CMMRD assessment, and phase confirmation was found in the case evidence.
BS3VCEPNot assessed: no governing VCEP file contains benign functional odds, NMD-inhibited RNA data, or proficient protein/mRNA results for c.903+4T>A.
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Reasoning
The ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP PMS2 specification v2.0 requires calibrated functional odds <=0.05, or for this intronic variant a laboratory assay showing no mRNA aberration with nonsense-mediated decay inhibition, or variant-specific proficient protein and mRNA function under the MMR functional assay flowchart. The variant NM_000535.7:c.903+4T>A (NP_000526.2:p.?) was searched in Functional-assay-SVI-documentation-MMR.xlsx.txt and Functional-assay-flowchart.pdf.txt using c.903+4T>A and p.?; neither file contains a variant-specific entry. No calibrated benign functional odds, NMD-inhibited RNA assay, proficient protein assay, or variant-specific mRNA/protein result is present in the case evidence. Therefore BS3 cannot be assessed; no matching VCEP-file entry is a gap, not evidence of benign function.
Evidence considered
VCEP CSPEC BS3 rule: calibrated functional assays with functional odds for Pathogenicity <=0.05, or synonymous/intronic variants with no mRNA aberration determined with nonsense-mediated decay inhibition, support Strong; calibrated odds >0.05 and <=0.48 or variant-specific proficient protein and mRNA-based assays under the MMR flowchart support Supporting.
Functional-assay-SVI-documentation-MMR.xlsx, sheet 'MMR assays': lists validated MMR assays, controls, readout thresholds, and proposed PS3/BS3 strengths, but no row for c.903+4T>A or p.?.
Functional-assay-flowchart.pdf: for an intronic variant with no splicing impact, requires NMD inhibitors to establish proficient function; no variant-specific splicing, allelic-imbalance, protein, or mRNA result is present for this variant.
Still missing
No entry for c.903+4T>A or p.? was found in Functional-assay-SVI-documentation-MMR.xlsx.txt.
No entry for c.903+4T>A or p.? was found in Functional-assay-flowchart.pdf.txt.
No calibrated functional odds <=0.05, NMD-inhibited RNA assay, proficient protein assay, or variant-specific proficient mRNA/protein result is available in the case evidence.
BS4VCEPNot assessed: no non-segregation observations or combined Bayes Likelihood Ratio is available for comparison with the VCEP thresholds.
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Reasoning
The VCEP requires lack of co-segregation in a pedigree and a combined Bayes Likelihood Ratio below the applicable threshold for BS4 strength. The case evidence provides no qualifying non-segregating relatives, pedigree structure, meioses, phenotype/genotype discordance, or calculated combined Bayes Likelihood Ratio; therefore BS4 cannot be evaluated.
VCEP rule
Lack of co-segregation with disease in pedigree(s) with a combined\* Bayes Likelihood Ratio <0.05.
OR
Lack of co-segregation with disease in pedigree(s) with a combined\* Bayes Likelihood Ratio >0.05 & ≤0.48.
Evidence considered
No pedigree, informative non-segregation result, phenotype/genotype discordance, or combined Bayes Likelihood Ratio was identified in the case evidence reviewed.
Still missing
Pedigree with affected and unaffected tested relatives
Variant and phenotype status for each informative relative
Number of informative non-segregating meioses and families
BP5VCEPNot assessed: no qualifying MSS/no-MMR-loss tumors, inconsistent MMR loss, BRAF V600E, or MLH1 methylation result is available.
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Reasoning
The VCEP BP5 rule requires either at least 2 tumors for Supporting or at least 4 tumors for Strong meeting its MSS/no-MMR-loss or inconsistent MMR-loss conditions, or specified BRAF V600E/MLH1-methylation findings. The case evidence contains no qualifying tumor pathology, BRAF V600E result, or MLH1 methylation result, so BP5 cannot be assessed.
VCEP rule
2 or 3 tumors: CRC/Endometrial tumors with MSS and/or no loss of MMR protein expression and/or LS spectrum tumors<sup>d</sup> with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation.
OR
1 BRAF V600E (Colon only)/_MLH1_ methylation (in LS spectrum tumor only) with MSI-H/_MLH1_ loss.
Evidence considered
The PMS2 VCEP BP5 Supporting rule requires 2 or 3 qualifying tumors or 1 qualifying BRAF V600E/MLH1 methylation result; the Strong rule requires at least 4 qualifying tumors or at least 2 such molecular results.
No patient-specific tumor pathology or BRAF/MLH1 molecular results are present in the available case evidence.
Still missing
No patient-specific tumor count or MSS/MMR-protein-loss results are available.
No BRAF V600E result or MLH1 methylation result is available.
Not applicable · 13· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.903+4T>A is outside the VCEP's explicitly covered PVS1 splice positions, IVS +/-1 or +/-2, and no qualifying RNA-confirmed aberration is available.
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Reasoning
The variant is NM_000535.7:c.903+4T>A, an intronic +4 variant with predicted protein consequence NP_000526.2:p.? and no confirmed patient-RNA result establishing a splice aberration. The PMS2 VCEP PVS1 rule covers nonsense/frameshift PTCs, large genomic alterations, IVS +/-1 or +/-2 variants with specified exon-skipping or cryptic-splice consequences, or qualifying patient-RNA-confirmed aberrations; c.903+4 is outside the explicitly named IVS +/-1 or +/-2 category and none of the other named paths is established. The governing PVS1 decision tree likewise lists GT-AG 1,2 splice sites, not +4 variants. The exact variant notation c.903+4T>A and protein notation p.? were searched in both named VCEP reference files, with no matching row or pre-assigned code found.
VCEP rule
Nonsense/frameshift variant introducing Premature Termination Codon (PTC)<sup>a </sup> ≤ codon 798 in _PMS2_. Refer to Appendix for details.
OR
Large genomic alterations<sup>a</sup> of single or multi-exon size.
OR
Variants at IVS±1 or IVS±2**<sup>a,c </sup> ** where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD. Not to be combined with PP3 and not to be used for a confirmed splice defect (see PVS1 for variants where patient mRNA assays indicate splicing aberration). If exon skipping or use of a cryptic splice site preserves reading frame and the altered region is critical to protein function<sup>b</sup> then use PVS1_Strong. If exon skipping or use of a cryptic splice site disrupts reading frame and is NOT predicted to undergo NMD then use PVS1_Moderate.
OR
Variants where mRNA assays using RNA derived from patient constitutional biological samples indicate that the variant allele results in a splicing aberration (with evidence that the variant allele produces no full-length/reference transcript) leading to premature stop codon or in-frame deletion disrupting a functional domain<sup>b</sup> or protein conformation. Splicing aberration must be confirmed in a minigene assay or an additional RNA assay from an independent laboratory if it is a non-canonical splice site variant.
Evidence considered
Case normalization: NM_000535.7:c.903+4T>A; NP_000526.2:p.?; exon 8i; canonical_splice_consensus=false; no confirmed patient-RNA consequence is documented.
ClinGen InSiGHT PMS2 CSPEC PVS1 rule: the very-strong path names nonsense/frameshift PTCs, large genomic alterations, IVS +/-1 or IVS +/-2 variants with disruptive exon skipping or cryptic splicing and predicted NMD, or qualifying patient-RNA-confirmed aberrations; +4 is not named.
PVS1_DecisionTree_MMR.pdf, transcribed table: the splice-site rows are GT-AG 1,2 splice sites, with separate outcomes for NMD, non-NMD, and reading-frame preservation; no +4 row is present.
VCEP-pilot-variants---MMR.xlsx, all searchable rows: no c.903+4T>A or p.? matching row was found.
Still missing
No matching entry for c.903+4T>A or p.? was found in PVS1_DecisionTree_MMR.pdf.txt.
No matching entry for c.903+4T>A or p.? was found in VCEP-pilot-variants---MMR.xlsx.txt.
PS4VCEPNot applicable: the PMS2 VCEP explicitly designates PS4 as Not Applicable.
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Reasoning
The PMS2 VCEP explicitly marks PS4 as Not Applicable. Therefore case-control enrichment or affected-case prevalence evidence is not evaluated under this VCEP framework.
PM1VCEPNot applicable: the PMS2 VCEP explicitly marks PM1 Not Applicable, regardless of the separately listed functional-domain schematic.
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Reasoning
The governing PMS2 VCEP specification explicitly marks PM1 Not Applicable. The case vcep_materials.json domain_tables key has no PMS2 entry, and the separately declared MMR-Functional-domains.pdf.txt was searched for c.903+4T>A, p.?, and p.? without a variant-specific entry; neither source overrides the VCEP's explicit PM1 applicability decision.
VCEP rule
Not Applicable
Evidence considered
The PMS2 Version 2.0 CSPEC entry for PM1 has applicability Not Applicable.
vcep_materials.json has an empty domain_tables object for this case.
MMR-Functional-domains.pdf.txt was searched for c.903+4T>A, p.?, and p.?; no matching variant entry was found.
Still missing
No entry for c.903+4T>A, p.?, or p.? was found in MMR-Functional-domains.pdf.txt.
PM4VCEPNot applicable: the VCEP excludes PM4 and this intronic variant has no established in-frame protein-length change or stop-loss consequence.
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Reasoning
PM4 is explicitly marked Not Applicable by the PMS2 VCEP. This variant is intronic, has protein notation p.?, and does not establish an in-frame protein length change or stop-loss consequence. No PM4 pre-assigned code for c.903+4T>A or p.? was found in the searched VCEP pilot table.
VCEP rule
Not Applicable
Evidence considered
ClinGen InSiGHT PMS2 CSPEC marks PM4 applicability as Not applicable and states: Protein length change from an in-frame variant is not used due to lack of evidence.
Case normalization gives an intronic c.903+4T>A variant with NP_000526.2:p.? rather than an established in-frame deletion, insertion, or stop-loss change.
VCEP-pilot-variants---MMR.xlsx, all searchable rows: no c.903+4T>A or p.? matching row was found.
Still missing
No matching entry for c.903+4T>A or p.? was found in PVS1_DecisionTree_MMR.pdf.txt.
No matching entry for c.903+4T>A or p.? was found in VCEP-pilot-variants---MMR.xlsx.txt.
PM5N/ANot applicable: c.903+4T>A is intronic with protein consequence p.?, not a missense change at an amino-acid residue.
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Reasoning
The VCEP PM5 rule is restricted to a missense change at an amino acid residue compared with a different VCEP-classified missense change at that residue. NM_000535.7:c.903+4T>A is intronic, has the normalized protein consequence p.?, and does not define an amino-acid residue for PM5; the criterion is therefore not applicable.
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
The VCEP PM5 rule requires a missense change at an amino acid residue and excludes changes due to aberrant splicing.
Case normalization identifies NM_000535.7:c.903+4T>A as intronic with NP_000526.2:p.?; no amino-acid residue or missense consequence is available.
PP2VCEPNot applicable: the governing PMS2 VCEP explicitly marks PP2 Not Applicable.
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Reasoning
The governing PMS2 VCEP specification explicitly marks PP2 Not Applicable, so the generic missense-mechanism criterion cannot be assigned to this case.
VCEP rule
Not Applicable
Evidence considered
The PMS2 Version 2.0 CSPEC entry for PP2 has applicability Not Applicable.
PP5VCEPNot applicable: the PMS2 VCEP explicitly designates PP5 as Not Applicable.
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Reasoning
The PMS2 VCEP explicitly marks PP5 as Not Applicable. ClinVar classifications and literature statements therefore do not generate PP5 under this governing framework.
BP3VCEPNot applicable: the VCEP excludes BP3, and c.903+4T>A is intronic rather than an in-frame deletion or insertion in a functionless repetitive region.
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Reasoning
BP3 is explicitly marked Not Applicable by the PMS2 VCEP. The variant is intronic with protein notation p.? and is not an established in-frame deletion or insertion in a repetitive region without known function. No BP3 pre-assigned code for c.903+4T>A or p.? was found in the searched VCEP pilot table.
VCEP rule
Not Applicable
Evidence considered
ClinGen InSiGHT PMS2 CSPEC marks BP3 applicability as Not applicable and states: In-frame deletions/insertions in a repetitive region without a known function is not used.
Case normalization gives an intronic c.903+4T>A variant with NP_000526.2:p.? rather than an established in-frame deletion or insertion.
VCEP-pilot-variants---MMR.xlsx, all searchable rows: no c.903+4T>A or p.? matching row was found.
Still missing
No matching entry for c.903+4T>A or p.? was found in PVS1_DecisionTree_MMR.pdf.txt.
No matching entry for c.903+4T>A or p.? was found in VCEP-pilot-variants---MMR.xlsx.txt.
BP6VCEPNot applicable: the PMS2 VCEP explicitly designates BP6 as Not Applicable.
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Reasoning
The PMS2 VCEP explicitly marks BP6 as Not Applicable. Benign assertions from non-VCEP sources therefore do not generate BP6 under this governing framework.
BP7N/ANot applicable: c.903+4T>A is an intronic +4 variant, inside the VCEP BP7 boundary of at or beyond +7.
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Reasoning
The VCEP BP7 rule covers a synonymous variant or an intronic variant at or beyond -21/+7, meaning at least 21 bases into the 5' intron or at least 7 bases into the 3' intron. c.903+4T>A is an intronic +4 variant and is inside the +7 boundary, so it is outside BP7 scope regardless of its SpliceAI score.
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
The variant is NM_000535.7:c.903+4T>A, an intronic +4 substitution.
The VCEP BP7 applicability boundary is at or beyond -21/+7; +4 is within the boundary and therefore outside the criterion's scope.
AF 6.1e-05 · 98 / 1,606,818 alleles · 2 hom · FAF 0.00072
South Asian80 / 90,948
0.000882 hom
Remaining individuals13 / 62,208
0.00021
African/African American1 / 74,790
1.3e-05
European (non-Finnish)4 / 1,173,502
3.4e-06
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00012 · 33 / 282,508 alleles · 0 hom · FAF 0.00073
South Asian31 / 30,594
0.001
Remaining individuals1 / 7,212
0.00014
African/African American1 / 24,916
4e-05
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.09901e-05; MAF= 0.00610%, 98/1606818 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.000879624; MAF= 0.08796%, 80/90948 alleles, homozygotes = 2); grpmax FAF= 0.00072347.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000116811; MAF= 0.01168%, 33/282508 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00101327; MAF= 0.10133%, 31/30594 alleles, homozygotes = 0); grpmax FAF= 0.00073312.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -334 bp
0.000
SpliceAI acceptor gainat +103 bp
0.209
SpliceAI donor lossat +3 bp
0.000
SpliceAI donor gainat +4 bp
0.138
Pangolin splice lossmagnitude shown
-0.003
Pangolin splice gain
0.165
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3SupportingVCEPMet: SpliceAI maximum delta score 0.209 meets the VCEP threshold of >=0.2 for a non-canonical splice variant.
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Reasoning
The variant is intronic at c.903+4T>A, a non-canonical splice position. The PMS2 VCEP permits PP3 Supporting for a predicted splice defect at a non-canonical splicing nucleotide when SpliceAI delta score is >= 0.2. The available SpliceAI result has DS_AG 0.209 and DS_DG 0.138, with maximum delta score 0.209; therefore the named predictor and cutoff are satisfied. The HCI missense-prior path is outside scope for this intronic variant, and a search of HCI-PRIORS-PMS2.txt.txt found no exact c.903+4T>A or p.? entry, but the VCEP's separate splice-prediction path is met.
VCEP rule
Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.
Evidence considered
SpliceAI result for NM_000535.7:c.903+4T>A: DS_AG=0.209, DS_DG=0.138, maximum delta score=0.209.
The VCEP rule's named splice path applies to non-canonical splicing nucleotides and requires SpliceAI delta score >= 0.2; the observed maximum is 0.209.
HCI-PRIORS-PMS2.txt.txt was searched for c.903+4T>A, c.903, and p.?; no exact variant entry was found.
Still missing
HCI-PRIORS-PMS2.txt.txt was searched for c.903+4T>A, c.903, and p.?; no exact entry was found. This missense-only lookup is not needed for the met intronic SpliceAI path.
BP4VCEPNot met: SpliceAI maximum delta score 0.209 exceeds the VCEP no-impact threshold of <=0.1.
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Reasoning
The variant is intronic, so the VCEP's intronic/synonymous BP4 path is applicable. That path requires SpliceAI to predict no splicing impact with delta score <= 0.1. SpliceAI reports a maximum delta score of 0.209, including DS_AG 0.209 and DS_DG 0.138, so the no-impact cutoff is not satisfied. The HCI missense-prior path is outside scope for this intronic variant; a search of HCI-PRIORS-PMS2.txt.txt found no exact c.903+4T>A or p.? entry.
VCEP rule
For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.
Evidence considered
SpliceAI result for NM_000535.7:c.903+4T>A: DS_AG=0.209, DS_DG=0.138, maximum delta score=0.209.
The VCEP intronic/synonymous BP4 path requires SpliceAI delta score <= 0.1; the observed maximum score is 0.209.
HCI-PRIORS-PMS2.txt.txt was searched for c.903+4T>A, c.903, and p.?; no exact variant entry was found.
Still missing
HCI-PRIORS-PMS2.txt.txt was searched for c.903+4T>A, c.903, and p.?; no exact entry was found. The missense-prior path is outside scope for this intronic variant.
BP7N/ANot applicable: c.903+4T>A is an intronic +4 variant, inside the VCEP BP7 boundary of at or beyond +7.
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Reasoning
The VCEP BP7 rule covers a synonymous variant or an intronic variant at or beyond -21/+7, meaning at least 21 bases into the 5' intron or at least 7 bases into the 3' intron. c.903+4T>A is an intronic +4 variant and is inside the +7 boundary, so it is outside BP7 scope regardless of its SpliceAI score.
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
The variant is NM_000535.7:c.903+4T>A, an intronic +4 substitution.
The VCEP BP7 applicability boundary is at or beyond -21/+7; +4 is within the boundary and therefore outside the criterion's scope.
SpliceAI predicts possible splice impact for this variant (max delta score = 0.21).
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
Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.
Giardiello FM et al. · 2014
This guideline states that germline PMS2 mutations can cause Lynch syndrome and discusses cancer-risk and diagnostic context, but it does not report this variant or provide variant-specific phenotype, tumor-testing, or case-control evidence.
Germline mutation in the MMR genes MLH1, MSH2 , MSH6 , and PMS2 cause LS ( 10,76 – 79 ).
Genetic Alterations—Germline mutations
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.
This general ACMG/AMP guidance explains that splice-site variants can cause exon skipping, exon shortening, or intronic-sequence inclusion and that functional RNA or protein analysis is needed to confirm impact; it does not report PMS2 c.903+4T>A or a variant-specific assay.
For splice site variants, the variant may lead to exon skipping, shortening or inclusion of intronic material, due to alternative donor/acceptor site usage or creation of new sites. Although splice site variants are predicted to lead to a null effect, confirmation of impact requires functional analysis by either RNA or protein analysis.
Proposed Criteria for Interpretation of Sequence Variants, PVS1 Null variants; PS3/BS3 Functional studies
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
This broad retrospective analysis notes that noncanonical intronic variants at +3 to +5 can affect splicing, but it provides no PMS2 c.903+4T>A observation or variant-specific functional result.
Variants predicted to affect splicing outside of the consensus sites occurred in the +3 to +5 range at the beginning of introns, and from −3 to −10 at the end of introns.
Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines.
Stoffel EM et al. · 2015
This guideline identifies PMS2 as a Lynch-syndrome mismatch-repair gene and describes MSI and corresponding MMR-protein loss at the syndrome level, but it does not report this variant or provide patient-specific PP4 or BP5 evidence.
The syndrome is characterized by an autosomal-dominant inheritance pattern and is associated with germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2, and EPCAM/TACSTD1 (ASCO addition). These alterations convey a predisposition to develop tumors with phenotypes of DNA microsatellite instability (MSI),3 which often demonstrate loss of expression of the corresponding MMR protein detected by immunohistochemistry (IHC) techniques.4,5
LS section, page 4
Lynch Syndrome: A Primer for Urologists and Panel Recommendations.
Mork M et al. · 2015
This review identifies PMS2 among Lynch-syndrome mismatch-repair genes and discusses MMR-protein immunohistochemistry, but it does not report this variant or provide variant-specific phenotype or tumor-testing evidence.
LS is caused by germline mutations in the MMR genes MLH1, MSH2 (and its modifier EPCAM ), MSH6 and PMS2. Pathogenic mutations in these genes lead to the accumulation of DNA errors in replicating cells, notably in microsatellite regions.
Results, “LS Genetics and Neoplasm Spectrum”
Genetics of Colorectal Cancer (PDQ®): Health Professional Version.
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= 6.09901e-05; MAF= 0.00610%, 98/1606818 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.000879624; MAF= 0.08796%, 80/90948 alleles, homozygotes = 2); grpmax FAF= 0.00072347.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000116811; MAF= 0.01168%, 33/282508 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00101327; MAF= 0.10133%, 31/30594 alleles, homozygotes = 0); grpmax FAF= 0.00073312.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (8 clinical laboratories) and as Benign (1 clinical laboratory) and as Likely Benign (1 clinical laboratory). (ClinVarID = 237931)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.21).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).