Variant classification summary

NM_000535.7:c.903+4T>A

PMS2 · NP_000526.2:p.? · NM_000535.7

GRCh37: chr7:6035161 A>T · GRCh38: chr7:5995530 A>T

Gene: PMS2 Transcript: NM_000535.7

Final call

VUS

PP3 supporting BS1 strong

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.?

gnomAD AF

6.099010591118596e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PP3 Supporting: SpliceAI maximum delta score 0.209 meets the VCEP threshold of at least 0.2 for a non-canonical splice variant.

2

BS1 Strong: gnomAD v4.1 Grpmax filtering allele frequency 0.00072347 falls within the VCEP BS1 interval.

Final determination: Under the PMS2 VCEP framework, one Strong benign criterion requires at least one additional benign Supporting criterion for Likely Benign, and the applied PP3 is pathogenic Supporting rather than benign, so no benign or pathogenic combination rule is satisfied and the call is VUS.

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	Not 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.	cspec vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PS1	Not assessed	Not assessed: SpliceAI max delta is 0.209, but no confirmed Pathogenic comparator at the same non-canonical splice nucleotide was found.	cspec spliceai vcep_mmr_functional_domains
PS2	Not assessed	Not assessed: no documented de novo event, parental confirmation, Lynch-spectrum tumor testing, or assignable de novo points are available.	cspec
PS3	Not assessed	Not assessed: the two governing VCEP functional files contain no variant-specific assay result, functional odds, or RNA finding for c.903+4T>A.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PS4	N/A	Not applicable: the PMS2 VCEP explicitly designates PS4 as Not Applicable.	cspec
PM1	N/A	Not applicable: the PMS2 VCEP explicitly marks PM1 Not Applicable, regardless of the separately listed functional-domain schematic.	cspec vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 total allele frequency is 0.0000609901, above the VCEP's <0.00002 PM2 threshold.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, pathogenic-in-trans, phase, or inheritance observations are available to assign the VCEP's PM3 point total.	cspec
PM4	N/A	Not applicable: the VCEP excludes PM4 and this intronic variant has no established in-frame protein-length change or stop-loss consequence.	cspec vcep_vcep_pilot_variants_mmr
PM5	N/A	Not applicable: c.903+4T>A is intronic with protein consequence p.?, not a missense change at an amino-acid residue.	cspec
PM6	N/A	Not applicable: the PMS2 VCEP explicitly designates PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no qualifying pedigree segregation data or combined Bayes Likelihood Ratio is available for comparison with the VCEP thresholds.	cspec
PP2	N/A	Not applicable: the governing PMS2 VCEP explicitly marks PP2 Not Applicable.	cspec
PP3	Met	Met: SpliceAI maximum delta score 0.209 meets the VCEP threshold of >=0.2 for a non-canonical splice variant.	cspec spliceai vcep_hci_priors_pms2
PP4	Not assessed	Not assessed: no qualifying MSI-H tumor, MMR-protein-loss result, or CMMRD phenotype is available to meet the PP4 rule.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
PP5	N/A	Not applicable: the PMS2 VCEP explicitly designates PP5 as Not Applicable.	cspec
BA1	Not met	Not met: gnomAD v4.1 Grpmax filtering allele frequency is 0.00072347, below the VCEP's 0.0028 BA1 threshold.	cspec gnomad_v4
BS1	Met	Met, Strong: gnomAD v4.1 Grpmax filtering allele frequency is 0.00072347, within the VCEP's 0.00028 to <0.0028 BS1 interval.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no documented qualifying in-trans co-occurrence, cancer-age evidence, CMMRD assessment, or parental/offspring phase confirmation is available.	cspec
BS3	Not assessed	Not assessed: no governing VCEP file contains benign functional odds, NMD-inhibited RNA data, or proficient protein/mRNA results for c.903+4T>A.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	Not assessed: no non-segregation observations or combined Bayes Likelihood Ratio is available for comparison with the VCEP thresholds.	cspec
BP1	N/A	Not applicable: the governing PMS2 VCEP explicitly marks BP1 Not Applicable.	cspec
BP2	N/A	Not applicable: the PMS2 VCEP specification explicitly designates BP2 as Not Applicable.	cspec
BP3	N/A	Not 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.	cspec vcep_vcep_pilot_variants_mmr
BP4	Not met	Not met: SpliceAI maximum delta score 0.209 exceeds the VCEP no-impact threshold of <=0.1.	cspec spliceai vcep_hci_priors_pms2
BP5	Not assessed	Not assessed: no qualifying MSS/no-MMR-loss tumors, inconsistent MMR loss, BRAF V600E, or MLH1 methylation result is available.	cspec
BP6	N/A	Not applicable: the PMS2 VCEP explicitly designates BP6 as Not Applicable.	cspec
BP7	N/A	Not applicable: c.903+4T>A is an intronic +4 variant, inside the VCEP BP7 boundary of at or beyond +7.	cspec

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