Variant classification summary

NM_000535.7:c.705+24C>T

PMS2 · NP_000526.2:p.? · NM_000535.7

GRCh37: chr7:6038715 G>A · GRCh38: chr7:5999084 G>A

Gene: PMS2 Transcript: NM_000535.7

Final call

Likely Benign

PM2 supporting BP4 supporting benign BP7 supporting benign

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.?

gnomAD AF

1.1797402584500449e-05 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000535.7:c.705+24C>T is an intronic variant in PMS2 located at position +24 of intron 6, outside the canonical splice consensus region.

2

This variant is present in gnomAD v4.1 at an extremely low overall allele frequency of 1.18e-05 (19/1,610,524 alleles, no homozygotes), meeting PM2_Supporting per InSiGHT PMS2 VCEP criteria (allele frequency <0.00002).

3

SpliceAI predicts no splicing impact with a maximum delta score of 0.04, meeting BP4_Supporting per the InSiGHT PMS2 VCEP (delta ≤0.1 for intronic variants).

4

The variant is at intronic position +24, which is beyond the +7 canonical splice donor boundary, meeting BP7_Supporting per the InSiGHT PMS2 VCEP (intronic variants at or beyond -21/+7).

5

The variant is absent from ClinVar and no publications were identified that mention NM_000535.7:c.705+24C>T.

6

The variant has been observed in COSMIC (COSV113734575, n=2 somatic occurrences), but this does not constitute germline evidence of pathogenicity.

7

Criteria met: PM2_Supporting (extremely rare in population databases). Benign criteria met: BP4_Supporting (SpliceAI predicts no splice impact), BP7_Supporting (intronic variant beyond canonical splice region).

8

Per InSiGHT PMS2 VCEP v2.0.0 combination Rule 31, the co-occurrence of pathogenic supporting evidence (PM2) and benign supporting evidence (BP4, BP7) results in Uncertain Significance — Conflicting Evidence. While the variant also satisfies Rule 19 (≥2 benign supporting criteria for Likely Benign), the presence of pathogenic supporting evidence triggers the conflicting evidence rule.

Final determination: Rule19 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 Likely Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

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

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_000535.7:c.705+24C>T is an intronic variant at position +24 in intron 6 of PMS2. This variant does not fall into any PVS1 null-variant category (nonsense, frameshift, or canonical ±1,2 splice consensus). The VCEP PVS1 criteria for PMS2 are limited to nonsense/frameshift variants introducing PTC, large genomic alterations, IVS±1/±2 splice variants, and initiation codon variants.	pvs1_variant_assessment pvs1_gene_context cspec
PS1	Not met	PS1 requires either a predicted missense substitution encoding the same amino acid change as a previously established pathogenic variant, or a variant affecting the same non-canonical splice nucleotide as a confirmed pathogenic splice variant with similar or worse SpliceAI prediction. NM_000535.7:c.705+24C>T is an intronic variant with SpliceAI max delta score of 0.04 (no predicted splice impact). No pathogenic variant has been established at the c.705+24 nucleotide position in PMS2.	cspec spliceai
PS2	Not met	No de novo observations are available for NM_000535.7:c.705+24C>T. The variant is absent from ClinVar and no publications report de novo occurrence. PS2 requires confirmed de novo status (maternity and paternity confirmed) in a proband with MMR-deficient LS spectrum tumor.	cspec
PS3	Not met	No functional assay data are available for NM_000535.7:c.705+24C>T. The VCEP functional assay documentation and pilot variants spreadsheet do not include this variant. No calibrated functional odds, MMR function assay results, or monoallelic expression data exist for this variant.	cspec vcep_functional_assay_svi_documentation_mmr vcep_vcep_pilot_variants_mmr
PS4	N/A	PS4 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0.	cspec
PS5	Not met	PS5 is not a defined criterion in the InSiGHT PMS2 VCEP v2.0.0 framework. Under generic ACMG/AMP, PS5 requires a different pathogenic variant at the same nucleotide position established by a reputable source. No such variant has been identified at c.705+24 in PMS2. The variant is absent from ClinVar.	cspec clinvar
PM1	N/A	PM1 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0.	cspec
PM2	Met	NM_000535.7:c.705+24C>T has an overall allele frequency of 1.18e-05 (19/1,610,524 alleles) in gnomAD v4.1, which is below the VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD-Canada v1.0. Per the InSiGHT PMS2 VCEP v2.0.0, this meets PM2_Supporting.	gnomad_v4 cspec
PM3	N/A	PM3 requires observation of the variant in trans with a pathogenic variant. Per user directive, this criterion is trivially not applicable for this case context.
PM4	N/A	PM4 requires a protein-length changing variant (in-frame deletion/insertion, stop-loss, or initiation codon change). NM_000535.7:c.705+24C>T is an intronic substitution with no protein consequence.
PM5	N/A	PM5 requires a missense change at an amino acid residue where a different missense change has been classified. NM_000535.7:c.705+24C>T is an intronic variant and does not encode an amino acid change. PM5 is not applicable to intronic variants.	pm5_candidates cspec
PM6	N/A	PM6 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0.	cspec
PP1	Not met	No co-segregation data are available for NM_000535.7:c.705+24C>T. The variant is absent from ClinVar and no publications report segregation analysis. PP1 requires co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio exceeding specified thresholds.	cspec
PP2	N/A	PP2 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0 (missense variant in a gene with low rate of benign missense changes does not apply).	cspec
PP3	Not met	PP3 in the InSiGHT PMS2 VCEP requires either an HCI prior score >0.68 for missense variants or a SpliceAI delta score ≥0.2 for non-canonical splice variants. NM_000535.7:c.705+24C>T is an intronic variant (not missense) with HCI prior not available. SpliceAI max delta score is 0.04, which falls below the 0.2 threshold for predicted splice defects. PP3 is not met.	cspec spliceai
PP4	Not met	No tumor phenotype data are available for NM_000535.7:c.705+24C>T. The variant is absent from ClinVar and no publications report MSI status, MMR protein expression, or tumor characteristics. PP4 requires evidence of MSI-H tumors and/or loss of MMR protein expression consistent with the variant location.	cspec
PP5	N/A	PP5 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0.	cspec
BA1	Not met	The gnomAD v4.1 grpmax filtering allele frequency for NM_000535.7:c.705+24C>T is 3.59e-05 (0.00359%), which is far below the VCEP BA1 threshold of ≥0.0028 (0.28%). BA1 is not met.	gnomad_v4 cspec
BS1	Not met	The gnomAD v4.1 grpmax filtering allele frequency for NM_000535.7:c.705+24C>T is 3.59e-05 (0.00359%), which is below the VCEP BS1 threshold range of ≥0.00028 and <0.0028 (0.028%-0.28%). BS1 is not met.	gnomad_v4 cspec
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 features. No such data are available. The variant is absent from ClinVar and no publications report trans co-occurrence data.	cspec
BS3	Not met	BS3 requires calibrated functional assays showing benign functional odds (≤0.05 for Strong, >0.05 & ≤0.48 for Supporting), or for intronic variants, laboratory assays demonstrating no associated mRNA aberration with NMD inhibition. No functional studies have been performed on NM_000535.7:c.705+24C>T. The SpliceAI delta of 0.04 predicts no splicing impact but is an in silico tool, not a laboratory assay, and is addressed under BP4.	cspec vcep_functional_assay_svi_documentation_mmr
BS4	Not met	No co-segregation data are available for NM_000535.7:c.705+24C>T. BS4 requires lack of co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio below specified thresholds. No family studies have been reported.	cspec
BP1	N/A	BP1 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0 (missense variant in a gene where only loss of function causes disease is not applicable).	cspec
BP2	N/A	BP2 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0.	cspec
BP3	N/A	BP3 is not applicable — this is an intronic substitution, not an in-frame deletion/insertion in a repetitive region.	cspec
BP4	Met	NM_000535.7:c.705+24C>T is an intronic variant. SpliceAI predicts no splicing impact with a maximum delta score of 0.04, which is ≤0.1. Per the InSiGHT PMS2 VCEP v2.0.0, intronic variants with SpliceAI delta ≤0.1 meet BP4_Supporting (Walker et al. 2023).	spliceai cspec
BP5	Not met	No tumor phenotype data are available for NM_000535.7:c.705+24C>T. BP5 requires evidence of MSS tumors and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation in appropriate tumor contexts. No such data have been reported.	cspec
BP6	N/A	BP6 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0.	cspec
BP7	Met	NM_000535.7:c.705+24C>T is an intronic variant located at position +24 in intron 6 of PMS2, which is beyond the +7 canonical splice donor boundary. Per the InSiGHT PMS2 VCEP v2.0.0, intronic variants at or beyond -21/+7 meet BP7_Supporting. This criterion may be combined with BP4 as noted in the VCEP rule.	cspec

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