Variant classification summary

NM_000535.7:c.33T>C

PMS2 · NP_000526.2:p.(Pro11=) · NM_000535.7

GRCh37: chr7:6045653 A>G · GRCh38: chr7:6006022 A>G

Gene: PMS2 Transcript: NM_000535.7

Final call

PM2 supporting BP4 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Pro11=)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000535.7:c.33T>C (p.Pro11=) is a synonymous variant in exon 2 of PMS2. It is absent from gnomAD v4.1, meeting PM2_Supporting under the InSiGHT VCEP v2.0.0 framework (allele frequency < 0.00002).

2

SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00, ≤ 0.1), meeting BP4_Supporting under the InSiGHT VCEP v2.0.0 framework.

3

ClinVar records this variant as Likely benign (4 submissions from clinical laboratories; ClinVar Variation ID 525878), though the review status is criteria provided, single submitter and this alone does not constitute an independent ACMG criterion under the VCEP framework.

4

No functional studies, segregation data, tumor phenotype data, or variant-specific literature were identified for NM_000535.7:c.33T>C. Multiple criteria (PS3, BS3, PP1, PP4, BS4, BP5) could not be assessed due to absence of evidence.

5

Applying the InSiGHT MMR VCEP v2.0.0 combination rules: PM2_Supporting (pathogenic supporting) and BP4_Supporting (benign supporting) are both met. With one pathogenic supporting and one benign supporting criterion and no criteria at higher strength levels, the combination rules do not yield a definitive classification. This results in a classification of Uncertain Significance.

Final determination: Rule31 in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 2.0.0 v2.0.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Uncertain Significance - Conflicting Evidence.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Synonymous variant (p.Pro11=) does not introduce a premature termination codon, is not at a canonical splice site, and does not fit any PVS1 null-variant bucket in the InSiGHT MMR VCEP v2.0.0 framework.
PS1	N/A	PS1 requires a missense substitution encoding the same amino acid change as a known pathogenic variant, or a variant affecting a non-canonical splice nucleotide matching a pathogenic splice variant. This is a synonymous variant (p.Pro11=) encoding no amino acid change and is not at a splice nucleotide.
PS2	Not met	No de novo observations reported for NM_000535.7:c.33T>C. De novo scoring (0 points) does not meet any PS2 strength threshold under the InSiGHT MMR VCEP v2.0.0 framework.
PS3	Not assessed	No calibrated functional assay data or MMR functional assay results are available for NM_000535.7:c.33T>C. Functional assessment cannot be performed without variant-specific experimental evidence.
PS4	N/A	PS4 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification.	cspec
PS5	N/A	PS5 is not included in the InSiGHT MMR VCEP v2.0.0 criteria set for PMS2 and is not used in this framework.	cspec
PM1	N/A	PM1 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification.	cspec
PM2	Met	NM_000535.7:c.33T>C is absent from gnomAD v4.1 (0 alleles), meeting the InSiGHT VCEP PM2_Supporting threshold of allele frequency < 0.00002 (<1 in 50,000 alleles).	gnomad_v4
PM5	N/A	PM5 requires a missense change at an amino acid residue where a different missense change is classified as Pathogenic or Likely Pathogenic. NM_000535.7:c.33T>C is a synonymous variant (p.Pro11=) and does not alter the amino acid.
PM6	N/A	PM6 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification.	cspec
PP1	Not assessed	No co-segregation data are available for NM_000535.7:c.33T>C. Co-segregation analysis with Bayes Likelihood Ratio cannot be performed.
PP2	N/A	PP2 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification.	cspec
PP3	Not met	PP3 under the InSiGHT VCEP requires either a missense variant with HCI prior probability > 0.68, or a predicted splice defect at non-canonical splice nucleotides with SpliceAI delta ≥ 0.2. NM_000535.7:c.33T>C is a synonymous variant not represented in the HCI prior table, and SpliceAI predicts no splicing impact (max delta = 0.00). Neither pathway is satisfied.	spliceai
PP4	Not assessed	No tumor MSI/IHC data are available for patients carrying NM_000535.7:c.33T>C. PP4 requires CRC/endometrial MSI-H tumors with MMR protein expression loss consistent with variant location.
PP5	N/A	PP5 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification.	cspec
BA1	Not met	BA1 requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.0028 (0.28%). NM_000535.7:c.33T>C is absent from gnomAD v4.1 and does not meet this threshold.	gnomad_v4
BS1	Not met	BS1 requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.00028 and < 0.0028. NM_000535.7:c.33T>C is absent from gnomAD v4.1 and does not meet this threshold.	gnomad_v4
BS2	Not met	BS2 requires co-occurrence in trans with a known pathogenic PMS2 variant in a patient with colorectal cancer after age 45 without CMMRD. No such co-occurrence has been reported for NM_000535.7:c.33T>C.
BS3	Not assessed	No calibrated functional assay data demonstrating proficient MMR function are available for NM_000535.7:c.33T>C. BS3 cannot be assessed without variant-specific functional evidence.
BS4	Not assessed	No segregation data are available to assess lack of co-segregation with disease for NM_000535.7:c.33T>C.
BP1	N/A	BP1 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification.	cspec
BP2	N/A	BP2 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification.	cspec
BP4	Met	NM_000535.7:c.33T>C is a synonymous variant and SpliceAI predicts no splicing impact (max delta score = 0.00, which is ≤ 0.1), meeting the InSiGHT VCEP BP4_Supporting threshold for intronic and synonymous variants.	spliceai
BP5	Not assessed	No tumor MSS/IHC data are available for patients carrying NM_000535.7:c.33T>C. BP5 requires CRC/endometrial tumors with MSS and/or no loss of MMR protein expression.
BP6	N/A	BP6 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification.	cspec
BP7	Not met	BP7 requires a synonymous variant at or within -21/+7 of the exon-intron boundaries (splice consensus region). NM_000535.7:c.33T>C is located at cDNA position 33, which is nucleotide +10 of exon 2 (exon 2 spans c.24 to c.163). Position +10 is beyond the +7 boundary from the 5' splice acceptor site and does not satisfy BP7.

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