NM_000535.7:c.23+32dup

PMS2 · NP_000526.2:p.? · NM_000535.7

GRCh37: chr7:6048595 A>AG · GRCh38: chr7:6008964 A>AG

Gene: PMS2 Transcript: NM_000535.7

Final call

Likely Benign

BP7 supporting BP4 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The PMS2 NM_000535.7:c.23+32dup (NP_000526.2:p.?) variant has been reported in ClinVar as likely benign by one clinical laboratory.

In gnomAD, this variant has a v4.1 total allele frequency of 5.0248e-05 (81/1612004 alleles) and a grpmax filtering allele frequency of 5.301e-05, which is above the PMS2 PM2 threshold of 0.00002 but below the BS1 threshold of 0.00028.

This intronic duplication is located at c.23+32, beyond the PMS2 BP7 boundary of +7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, supporting BP7 and BP4 while arguing against PP3 and PVS1.

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
PS1	Not assessed	No evidence was identified that this variant affects the same non-canonical splice nucleotide as a previously established pathogenic or likely pathogenic PMS2 splice variant with similar or worse predicted splicing impact.	cspec vcep_vcep_pilot_variants_mmr
PS2	Not assessed	No de novo data with the required tumor context or parental confirmation were identified, so this criterion cannot be assessed from the available evidence.	cspec
PP4	Not assessed	No MSI-high tumor findings or mismatch repair protein loss data consistent with PMS2 were identified, so phenotype-based support is not established.	cspec
BP3	N/A	BP3 is not used in this PMS2 VCEP framework.	cspec
BP7	Met	This intronic duplication is located at c.23+32, which is beyond the +7 intronic threshold specified for BP7, meeting the PMS2 VCEP location requirement for a benign supporting code.	cspec
BS2	Not assessed	No evidence was identified that this variant co-occurs in trans with a known pathogenic PMS2 variant in a person meeting the PMS2 VCEP conditions for BS2.	cspec vcep_table_for_cmmrd_diagnosis
BP4	Met	SpliceAI predicts no significant splice impact for this intronic duplication, with a maximum delta score of 0.02, which is below the PMS2 VCEP BP4 threshold of 0.1.	cspec spliceai
PP1	Not assessed	No segregation data were identified, so co-segregation support cannot be assessed.	cspec
PS3	Not assessed	No calibrated functional assay or constitutional RNA study demonstrating a damaging effect was identified for this variant.	cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
BA1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 5.301e-05 (0.005301%), which is below the PMS2 VCEP BA1 threshold of 0.0028 (0.28%), so BA1 is not met.	cspec gnomad_v4
PP2	N/A	PP2 is not used in this PMS2 VCEP framework.	cspec
BP1	N/A	BP1 is not used in this PMS2 VCEP framework.	cspec
BP6	N/A	BP6 is not applicable in this PMS2 VCEP framework.	cspec
PP5	N/A	PP5 is not applicable in this PMS2 VCEP framework.	cspec
BS4	Not assessed	No non-segregation data were identified, so BS4 cannot be assessed.	cspec
BS3	Not assessed	No functional or RNA evidence demonstrating no damaging effect was identified for this variant.	cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
PS4	N/A	PS4 is not used in this PMS2 VCEP framework.	cspec
PM4	N/A	PM4 is not used in this PMS2 VCEP framework.	cspec
BS1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 5.301e-05 (0.005301%), which is below the PMS2 VCEP BS1 range threshold of 0.00028 (0.028%), so BS1 is not met.	cspec gnomad_v4
PP3	Not met	SpliceAI predicts a maximum delta score of 0.02, which is below the PMS2 VCEP PP3 threshold of 0.2 for a predicted splice defect, so PP3 is not met.	cspec spliceai
PVS1	Not met	This deep intronic duplication does not fall within the PMS2 VCEP default PVS1 categories for nonsense, frameshift, canonical splice, or qualifying large rearrangement variants, and no patient RNA evidence was identified to show that the variant causes a loss-of-function splicing abnormality.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PM1	N/A	PM1 is not used in this PMS2 VCEP framework.	cspec
BP2	N/A	BP2 is not used in this PMS2 VCEP framework.	cspec
PM2	Not met	The gnomAD v4.1 total allele frequency is 5.0248e-05 (81/1612004 alleles; 0.00502%), which is above the PMS2 VCEP PM2 threshold of 0.00002 (1 in 50,000 alleles), so PM2 is not met.	cspec gnomad_v4 gnomad_v2
BP5	Not assessed	No tumor profile data were identified to show mismatch repair findings inconsistent with PMS2-associated disease, so BP5 cannot be assessed.	cspec
PM6	N/A	PM6 is not used in this PMS2 VCEP framework.	cspec
PM3	Not assessed	No observations were identified to score this variant in trans with another pathogenic PMS2 variant for the PMS2 VCEP PM3 point system.	cspec vcep_table_for_cmmrd_diagnosis
PM5	Not assessed	This is not a missense variant, and no evidence was identified to support applying a same-residue missense rule.	cspec

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