Variant classification summary

NM_000535.7:c.1239del

PMS2 · NP_000526.2:p.(Asp414ThrfsTer34) · NM_000535.7

GRCh37: chr7:6027156 CT>C · GRCh38: chr7:5987525 CT>C

Gene: PMS2 Transcript: NM_000535.7

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Asp414ThrfsTer34)

gnomAD AF

6.195809897682395e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PMS2 NM_000535.7:c.1239del (p.(Asp414ThrfsTer34), p.(D414Tfs*34)) variant has been reported in ClinVar as Pathogenic by 6 clinical laboratories.

2

This variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0 and is present only once in gnomAD v4.1 (AF 6.19581e-07; 1/1613994 alleles), which is below the PMS2 PM2_Supporting threshold of 0.00002.

3

This frameshift is predicted to introduce a premature termination codon after 34 altered amino acids, and the PMS2 VCEP specification applies PVS1 at very strong strength to frameshift variants with a premature stop at or before codon 798.

4

SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.02); however, the primary predicted effect remains a truncating frameshift rather than an isolated splice or missense change.

Final determination: No criteria-combination rule matched the adjudicated criteria 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 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	Met	This frameshift variant is predicted to cause p.(Asp414ThrfsTer34) and introduce a premature termination codon well before codon 798 in PMS2. Under the PMS2 VCEP specification, nonsense or frameshift variants introducing a premature stop at or before codon 798 meet PVS1 at very strong strength.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This criterion is not applicable because the variant is a frameshift deletion rather than a missense change or a non-canonical splice variant evaluated under the PMS2 PS1 rule.	cspec
PS2	Not assessed	No confirmed de novo occurrence data were identified for this variant, so PS2 cannot be applied.	clinvar
PS3	Not assessed	Available evidence supports a truncating loss-of-function interpretation, but no variant-specific calibrated functional assay result or qualifying RNA study was identified to support PS3 under the PMS2 VCEP rules.	oncokb cspec
PS4	N/A	This criterion is not applicable in the PMS2 VCEP specification.	cspec
PM1	N/A	This criterion is not applicable in the PMS2 VCEP specification.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0 and is present only once in gnomAD v4.1 (1/1613994 alleles; AF 6.19581e-07, 0.00006%), which is below the PMS2 VCEP PM2_Supporting threshold of 0.00002.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	No confirmed in trans observation with another pathogenic or likely pathogenic PMS2 variant was identified for this variant, so PM3 cannot be applied.	clinvar cspec
PM4	N/A	This criterion is not applicable in the PMS2 VCEP specification.	cspec
PM5	N/A	This criterion is not applicable because the PMS2 PM5 rule is for same-residue missense substitutions, and this variant is a frameshift deletion.	cspec pm5_candidates
PM6	N/A	This criterion is not applicable in the PMS2 VCEP specification.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	clinvar cspec
PP2	N/A	This criterion is not applicable in the PMS2 VCEP specification.	cspec
PP3	N/A	This criterion is not applicable because the PMS2 PP3 rule is for missense substitutions with HCI prior support or non-canonical splice variants with SpliceAI support, and this variant is a frameshift deletion. SpliceAI shows a low maximum delta score of 0.02, but that does not convert this frameshift into a PP3-eligible variant class.	cspec spliceai
PP4	Not assessed	No qualifying tumor MSI or mismatch repair immunohistochemistry data linked to this variant were identified, so PP4 cannot be applied.	cspec clinvar
PP5	N/A	This criterion is not applicable in the PMS2 VCEP specification.	cspec
BA1	Not met	Population frequency does not meet BA1. The highest available gnomAD v4.1 frequency is 6.19581e-07 overall (0.00006%; 1/1613994 alleles), which is far below the PMS2 BA1 threshold of 0.0028.	cspec gnomad_v4
BS1	Not met	Population frequency does not meet BS1. The highest available gnomAD v4.1 frequency is 6.19581e-07 overall (0.00006%; 1/1613994 alleles), which is below the PMS2 BS1 threshold of 0.00028.	cspec gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in trans with a known pathogenic PMS2 variant in an older individual without features of constitutional mismatch repair deficiency, so BS2 cannot be applied.	cspec
BS3	Not assessed	No variant-specific functional evidence demonstrating retained PMS2 function or normal RNA behavior was identified, so BS3 cannot be applied.	oncokb cspec
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 cannot be applied.	cspec clinvar
BP1	N/A	This criterion is not applicable in the PMS2 VCEP specification.	cspec
BP2	N/A	This criterion is not applicable in the PMS2 VCEP specification.	cspec
BP3	N/A	This criterion is not applicable in the PMS2 VCEP specification.	cspec
BP4	N/A	This criterion is not applicable because the PMS2 BP4 rule is limited to missense variants with HCI prior less than 0.11 or to synonymous/intronic variants with SpliceAI less than or equal to 0.1, and this variant is a frameshift deletion. Although SpliceAI predicts no significant splice impact (max delta score 0.02), that does not satisfy BP4 for this variant class.	cspec spliceai
BP5	Not assessed	No qualifying tumor findings inconsistent with PMS2-related disease were identified, so BP5 cannot be applied.	cspec
BP6	N/A	This criterion is not applicable in the PMS2 VCEP specification.	cspec
BP7	N/A	This criterion is not applicable because the variant is not synonymous and is not an intronic change at a BP7-eligible position.	cspec

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