PMS2 c.1567T>A, p.(Ser523Thr)

Reasoning

The ClinGen InSiGHT PMS2 VCEP specifies BS1 Strong when the gnomAD v4 grpmax filtering allele frequency is at least 0.00028 and less than 0.0028 (0.028–0.28%), and the variant is not an excluded founder pathogenic variant. The gnomAD v4.1 grpmax FAF is 0.00045665 (0.045665%), which falls within that interval; therefore BS1 Strong is met. The variant has no observed homozygotes, and the elevated South Asian frequency does not exceed the VCEP BS1-to-BA1 range.

Rule

PMS2 InSiGHT VCEP BS1 Strong: gnomAD v4 grpmax filtering allele frequency ≥0.00028 and <0.0028 (0.028–0.28%) and variant excluded as a founder pathogenic variant.

Evidence considered

• The PMS2 VCEP specifies BS1 Strong at gnomAD v4 grpmax filtering allele frequency ≥0.00028 and <0.0028 (0.028–0.28%), provided the variant is not an excluded founder pathogenic variant.
• gnomAD v4.1 reports grpmax FAF 0.00045665 (0.045665%), corresponding to 3 alleles in the highest grpmax population, and reports zero homozygotes.

Sources

Reasoning

This is a missense variant, and the governing PMS2 VCEP directly assigns BP4 Supporting when the HCI MAPP/PP2 Prior P score is <0.11. The exact HCI-PRIORS-PMS2 row for c.1567T>A (p.S523T) reports an HCI prior probability of 0.0008 and custom PP2 score of 0.031, both below the governing <0.11 cutoff. This direct VCEP assignment is used; SpliceAI is not used because the variant is missense.

Rule

PMS2 VCEP BP4 Supporting: missense variant with HCI MAPP/PP2 Prior P <0.11.

Evidence considered

• The governing PMS2 VCEP specifies BP4 Supporting for a missense variant with HCI MAPP/PP2 Prior P <0.11.
• The exact HCI-PRIORS-PMS2 row for c.1567T>A / p.S523T reports HCI prior probability 0.0008 and custom PP2 score 0.031, satisfying the VCEP BP4 rule.

Sources

Reasoning

The PMS2 VCEP PS1 rule requires a different nucleotide change producing the same amino-acid substitution that was previously established by the VCEP as Pathogenic, or a qualifying splice-site comparison. The target is NM_000535.7:c.1567T>A, p.Ser523Thr. PMID:17016615 reports a Ser523Thr substitution from a different nucleotide change (TCC to ACC, reported at nucleotide 1591) in 2 of 20 breast carcinomas, but it does not establish that comparator as VCEP-Pathogenic and the report is not a qualifying VCEP classification. No qualifying pathogenic same-amino-acid comparator was identified; therefore PS1 is not met.

Rule

A predicted missense substitution encoding the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic, and not a predicted or confirmed splice defect.

Evidence considered

• The PMS2 VCEP requires a same-amino-acid substitution from a different nucleotide that was established by the VCEP as Pathogenic.
• PMID:17016615 reports Ser523Thr from a different nucleotide change in 2 of 20 invasive breast carcinomas but does not establish the comparator as VCEP-Pathogenic.

Still missing

• No VCEP-established Pathogenic same-amino-acid comparator was identified.

Sources

Reasoning

The ClinGen InSiGHT PMS2 VCEP specifies PM2 Supporting for an absent or extremely rare allele frequency below 0.00002 (less than 1 in 50,000 alleles) in gnomAD v4. The gnomAD v4.1 all-comers total allele frequency is 0.000167304 (270/1,613,828 alleles), above the VCEP threshold; therefore PM2 is not met. The variant is also observed in multiple ancestry groups and has zero homozygotes, but the observed allele frequency is sufficient to preclude PM2.

Rule

PMS2 InSiGHT VCEP PM2 Supporting: absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4.

Evidence considered

• The PMS2 VCEP specifies PM2 Supporting for an absent or extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4.
• gnomAD v4.1 reports an overall AF of 0.000167304, based on 270 of 1,613,828 alleles, with zero homozygotes; the highest ancestry-specific AF is 0.000581995 in South Asian individuals.

Sources

Reasoning

The PMS2 VCEP PM5 rule requires a different missense change at the same amino-acid residue that was classified by the VCEP as Pathogenic or Likely Pathogenic at the protein level and not because of aberrant splicing; the rule also requires PP3 supporting for the target missense change. The residue is Ser523, but the collected comparator review found zero same-residue candidates, zero expert-panel Pathogenic/Likely Pathogenic candidates, and zero non-expert majority candidates. Therefore no qualifying comparator is available to apply PM5.

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; use only if PP3 is supporting. Use PM5 Supporting when the other variant is Likely Pathogenic, and PM5 when it is Pathogenic.

Evidence considered

• The PMS2 VCEP requires a different missense change at the same residue, classified as Pathogenic or Likely Pathogenic at the protein level and not due to aberrant splicing; PM5 also requires PP3 supporting for the target.
• The PM5 comparator review found zero same-residue candidates, including zero expert-panel or non-expert-majority Pathogenic/Likely Pathogenic candidates.

Still missing

• A qualifying VCEP-classified Pathogenic or Likely Pathogenic different missense change at residue Ser523 is not available.

Sources

Reasoning

This is a missense variant, so the PMS2 VCEP missense computational rule applies. The governing HCI-PRIORS-PMS2 entry for c.1567T>A (p.S523T) reports HCI prior probability 0.0008 and custom PP2 score 0.031, neither of which reaches the VCEP PP3 thresholds (>0.81 for Moderate or >0.68 and <=0.81 for Supporting). The available REVEL score is 0.262 and does not provide an independent basis to meet PP3. SpliceAI is not used for PP3 because this is a missense variant.

Rule

PMS2 VCEP PP3: missense variant with MAPP/PP2 Prior P >0.81 = Moderate, or >0.68 and <=0.81 = Supporting.

Evidence considered

• The governing PMS2 VCEP specifies PP3 Moderate for an HCI MAPP/PP2 Prior P score >0.81 and PP3 Supporting for >0.68 and <=0.81.
• The exact HCI-PRIORS-PMS2 row for c.1567T>A / p.S523T reports HCI prior probability 0.0008, MAPP score 2.35, and custom PP2 score 0.031.
• The case consequence is missense (PMS2 c.1567T>A, p.S523T), so SpliceAI is not an applicable PP3 path; the available REVEL score is 0.262 and does not meet the supplied generic PP3 Supporting threshold of 0.644 (ClinGen SVI calibration, PMID:36413997).

Sources

Reasoning

The ClinGen InSiGHT PMS2 VCEP specifies BA1 when the gnomAD v4 grpmax filtering allele frequency is at least 0.0028 (0.28%) and the variant is not an excluded founder pathogenic variant. The gnomAD v4.1 grpmax FAF for NM_000535.7:c.1567T>A is 0.00045665 (0.045665%), well below 0.0028; therefore BA1 is not met. The available population data also show no homozygotes, but this does not alter the BA1 conclusion.

Rule

PMS2 InSiGHT VCEP BA1: gnomAD v4 grpmax filtering allele frequency ≥0.0028 (0.28%) and variant excluded as a founder pathogenic variant.

Evidence considered

• The PMS2 VCEP specifies BA1 at gnomAD v4 grpmax filtering allele frequency ≥0.0028 (0.28%), provided the variant is not an excluded founder pathogenic variant.
• gnomAD v4.1 reports grpmax FAF 0.00045665 (0.045665%), with the highest population frequency in South Asian individuals at AF 0.000581995 and no homozygotes.

Sources

Reasoning

The PMS2 InSiGHT VCEP requires de novo points based on a proband with an LS-spectrum tumor: 2 points when both maternity and paternity are confirmed with MMR-deficient tumor data, 1 point when both are confirmed without tumor data, or 0.5 points when de novo status is assumed with maternity and/or paternity unconfirmed. The available case evidence provides no proband-level parental testing, maternity or paternity confirmation, de novo assertion, LS-spectrum tumor diagnosis, MSI/IHC result, or methylation result, so no de novo points can be assigned.

Rule

PMS2 InSiGHT VCEP v2.0 PS2: >=4 de novo points = Very Strong; 2-3.5 points = Strong; 1-1.5 points = Moderate; 0.5 points = Supporting.

Evidence considered

• The PMS2 InSiGHT VCEP version 2.0 assigns 2, 1, or 0.5 de novo points according to parental confirmation and LS-spectrum tumor evidence.
• The case materials contain no documented proband, parental testing, de novo status, or qualifying tumor findings for this variant.

Still missing

• Proband-level evidence that the variant is de novo
• Maternity and paternity testing status
• LS-spectrum tumor diagnosis and MSI/IHC/methylation results

Sources

Reasoning

The applicable InSiGHT PMS2 VCEP requires a calibrated functional assay with functional odds for pathogenicity >2.08 for PS3 Supporting, >4.3 and <=18.7 for PS3 Moderate, or >18.7 for PS3 Strong; alternatively, an MMR function defect may support PS3 Moderate. The available variant-specific literature identifies p.Ser523Thr only as a neutral in-silico PON-MMR prediction and reports no functional assay, MMR activity measurement, protein-expression study, or RNA assay for NM_000535.7:c.1567T>A. OncoKB likewise reports no variant-specific reviewed functional evidence. Therefore, PS3 cannot be assigned.

Rule

Calibrated functional assays with functional odds for Pathogenicity > 18.7 (Strong); >4.3 and <=18.7 or MMR function defect following the functional assay flowchart (Moderate); >2.08 and <=4.3 (Supporting).

Evidence considered

• The PMS2 InSiGHT VCEP specifies PS3 Supporting for calibrated functional odds >2.08 and <=4.3, Moderate for odds >4.3 and <=18.7 or an MMR function defect following the functional assay flowchart, and Strong for odds >18.7.
• PMS2 p.Ser523Thr is listed in PMID:22290698 as a neutral PON-MMR in-silico prediction; the paper reports no variant-specific functional assay or clinical functional result.
• OncoKB reports no variant-specific reviewed functional evidence for this variant.

Still missing

• A validated, variant-specific PMS2 functional assay with calibrated functional odds or an MMR function-defect assessment is unavailable.

Sources

Reasoning

The ClinGen InSiGHT PMS2 VCEP v2.0 applies PM3 using an allelic-observation point system: at least 4 points supports Very Strong, 2–3.5 Strong, 1–1.5 Moderate, and 0.5 Supporting. The reviewed case evidence does not document an affected proband with NM_000535.7:c.1567T>A in trans with a known pathogenic or likely pathogenic PMS2 variant, a confirmed homozygous state, or other qualifying phase-resolved biallelic observation. PMID:26232782 mentions c.1567T>A only as a PMS2/PMS2CL paralogous sequence variant and reports no clinical or segregation data for it; PMID:22290698 lists S523T as a neutral in-silico prediction without clinical, phase, or segregation observations. Therefore no PM3 points can be assigned from the available evidence.

Rule

PMS2 VCEP v2.0 PM3 point system: ≥4 points Very Strong; 2–3.5 Strong; 1–1.5 Moderate; 0.5 Supporting.

Evidence considered

• PMS2 VCEP v2.0 specifies PM3 point thresholds of ≥4 for Very Strong, 2–3.5 for Strong, 1–1.5 for Moderate, and 0.5 for Supporting.
• The report by Nomura et al. mentions c.1567T>A as a paralogous sequence variant during PMS2/PMS2CL sequencing, but does not report it as the patient's mutation or provide clinical, segregation, or phase data for this variant.
• The PON-MMR paper lists PMS2 S523T under neutral predictions and provides no clinical case, segregation, phase, or biallelic observation for this variant.

Still missing

• Affected-proband observations with the variant are needed.
• A confirmed pathogenic or likely pathogenic PMS2 allele in trans, or confirmed homozygosity, and phase evidence are needed to assign PM3 points.

Sources

Reasoning

The PMS2 InSiGHT VCEP requires a combined segregation Bayes likelihood ratio greater than 2.08 for Supporting, greater than 4.3 and up to 18.7 for Moderate, or greater than 18.7 in at least two families for Strong. No affected or unaffected relatives, pedigree, informative meioses, phenotype-linked genotypes, or calculated Bayes likelihood ratio are reported for NM_000535.7:c.1567T>A, so PP1 cannot be assigned.

Rule

PMS2 InSiGHT VCEP v2.0 PP1: combined Bayes likelihood ratio >18.7 in >=2 families = Strong; >4.3 and <=18.7 = Moderate; >2.08 and <=4.3 = Supporting.

Evidence considered

• The PMS2 InSiGHT VCEP sets PP1 thresholds at combined Bayes likelihood ratios >2.08 to 4.3 for Supporting, >4.3 to 18.7 for Moderate, and >18.7 in at least two families for Strong.
• The available case evidence reports no family segregation data or Bayes likelihood ratio for this variant.

Still missing

• Pedigree with affected and unaffected relatives
• Variant genotypes and disease phenotypes for informative relatives
• Combined segregation Bayes likelihood ratio

Sources

Reasoning

PP4 is applicable under the PMS2 VCEP, but the available case evidence does not provide a case-specific CRC or endometrial tumor count, MSI status, tumor-genome result, or PMS2-consistent loss of MMR protein expression. The exact-variant paper mentioning c.1567T>A identifies it only as a paralogous sequence variant and reports no phenotype or tumor result. Therefore the PP4 threshold cannot be assessed. The governing VCEP rules are: Strong requires ≥3 independent CRC/endometrial MSI-H tumors in ≥2 families with qualifying tumor testing and/or consistent MMR protein loss; Moderate requires 2 independent qualifying tumors; Supporting requires 1 qualifying tumor.

Rule

Supporting: 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. Moderate: 2 independent CRC/Endometrial MSI-H tumors using a standard panel of 5-10 markers or tumor genome and/or loss of MMR protein expression consistent with the variant location. Strong: ≥3 independent CRC/Endometrial MSI-H tumors in ≥2 families using a standard panel of 5-10 markers or tumor genome and/or loss of MMR protein expression consistent with the variant location.

Evidence considered

• The PMS2 VCEP defines PP4 Supporting as 1 qualifying CRC/endometrial MSI-H tumor, Moderate as 2 independent qualifying tumors, and Strong as ≥3 independent tumors in ≥2 families, with qualifying MSI/tumor-genome and/or MMR-protein evidence consistent with PMS2.
• PMID:26232782 mentions c.1567T>A only as a paralogous sequence variant during PMS2/PMS2CL sequencing and does not report a clinical phenotype, tumor MSI result, or MMR-protein result for this variant.

Still missing

• Case-specific tumor phenotype data are needed: tumor type, number of independent tumors and families, MSI or tumor-genome results, and PMS2-consistent MMR protein expression.

Sources

Reasoning

The PMS2 VCEP requires co-occurrence in trans with a known pathogenic sequence variant in PMS2, a colorectal cancer diagnosis after age 45 or another Lynch syndrome cancer above its median age of onset, absence of CMMRD manifestations, and parental or offspring testing to confirm phase. The available case evidence contains no qualifying individual-level co-occurrence, phenotype, CMMRD assessment, or confirmed phase data, so BS2 cannot be assessed.

Rule

PMS2 InSiGHT VCEP BS2 Strong: co-occurrence in trans with a known pathogenic PMS2 sequence variant in a patient with colorectal cancer after age 45 or another Lynch syndrome cancer above its median age of onset, without CMMRD manifestations; phase must be confirmed through parents or offspring.

Evidence considered

• The PMS2 VCEP BS2 rule requires in-trans co-occurrence with a known pathogenic PMS2 sequence variant, an age-qualified Lynch syndrome cancer phenotype, no prior or current CMMRD manifestations, and phase confirmation through parents or offspring.
• No qualifying individual-level co-occurrence, phenotype, CMMRD assessment, or confirmed phase evidence is present in the reviewed case materials.

Still missing

• A documented individual with this variant and a known pathogenic PMS2 variant confirmed in trans is needed.
• The required age-specific Lynch syndrome cancer phenotype and absence of CMMRD manifestations must be documented.
• Parental or offspring testing is needed to confirm phase.

Sources

Reasoning

The applicable InSiGHT PMS2 VCEP requires calibrated functional odds for pathogenicity <=0.05 for BS3 Strong or >0.05 and <=0.48 for BS3 Supporting; for missense variants, its flowchart also requires variant-specific proficient function in protein and mRNA-based laboratory assays for BS3 Supporting. The available evidence contains no variant-specific protein, RNA, MMR activity, expression, or calibrated functional assay for NM_000535.7:c.1567T>A. The PON-MMR neutral prediction is computational and cannot establish proficient function. Therefore, BS3 cannot be assigned.

Rule

Calibrated functional assays with functional odds for Pathogenicity <= 0.05 (Strong); >0.05 and <=0.48 or variant-specific proficient function in protein and mRNA-based laboratory assays (Supporting).

Evidence considered

• The PMS2 InSiGHT VCEP specifies BS3 Strong for calibrated functional odds for pathogenicity <=0.05 and BS3 Supporting for odds >0.05 and <=0.48, or variant-specific proficient function in protein and mRNA-based laboratory assays under the MMR functional assay flowchart.
• PMID:22290698 reports only a neutral computational PON-MMR prediction for S523T and provides no variant-specific functional assay demonstrating proficient protein or mRNA function.
• OncoKB reports no variant-specific reviewed functional evidence for this variant.

Still missing

• Variant-specific protein and mRNA-based laboratory assays or calibrated functional odds demonstrating proficient function are unavailable.

Sources

Reasoning

The PMS2 InSiGHT VCEP requires lack of co-segregation demonstrated by a combined Bayes likelihood ratio below 0.05 for Strong or greater than 0.05 and up to 0.48 for Supporting. No pedigree, affected-relative non-segregation, unaffected-carrier observation, informative meioses, or Bayes likelihood ratio is reported for NM_000535.7:c.1567T>A, so BS4 cannot be assigned.

Rule

PMS2 InSiGHT VCEP v2.0 BS4: combined Bayes likelihood ratio <0.05 = Strong; >0.05 and <=0.48 = Supporting.

Evidence considered

• The PMS2 InSiGHT VCEP sets BS4 thresholds at a combined Bayes likelihood ratio <0.05 for Strong and >0.05 to 0.48 for Supporting.
• The available case evidence reports no non-segregation observations or Bayes likelihood ratio for this variant.

Still missing

• Pedigree with disease status and variant genotypes
• Documented non-segregation in affected relatives
• Combined segregation Bayes likelihood ratio

Sources

Reasoning

BP5 is applicable under the PMS2 VCEP, but no case-specific evidence establishes the required benign tumor pattern. There are no reported counts of CRC/endometrial tumors with MSS or no MMR-protein loss, no LS-spectrum tumors with MMR-protein loss inconsistent with PMS2, and no qualifying BRAF V600E or MLH1-methylation result. Accordingly, neither the Supporting rule of 2 or 3 tumors or 1 qualifying BRAF/methylation result nor the Strong rule of ≥4 tumors or ≥2 qualifying BRAF/methylation results can be assessed. No numeric comparison is applicable to this qualitative tumor-count rule.

Rule

Supporting: 2 or 3 tumors with MSS and/or no loss of MMR protein expression and/or LS-spectrum tumors with loss of MMR protein(s) inconsistent with the gene demonstrating genetic variation, or 1 BRAF V600E/MLH1 methylation result with MSI-H/MLH1 loss. Strong: ≥4 such tumors, or ≥2 BRAF V600E/MLH1 methylation results with MSI-H/MLH1 loss.

Evidence considered

• The PMS2 VCEP defines BP5 Supporting as 2 or 3 qualifying tumors or 1 qualifying BRAF V600E/MLH1-methylation result, and Strong as ≥4 qualifying tumors or ≥2 such results; none is documented for this case.

Still missing

• Case-specific benign tumor evidence is needed: qualifying tumor count and pathology, MMR-protein expression, MSI status, and any BRAF V600E or MLH1-methylation results.

Sources