Variant classification summary

NM_000535.7:c.241G>A

PMS2 · NP_000526.2:p.(Glu81Lys) · NM_000535.7

GRCh37: chr7:6043612 C>T · GRCh38: chr7:6003981 C>T

Gene: PMS2 Transcript: NM_000535.7

Final call

VUS

BP4 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Glu81Lys)

gnomAD AF

3.2622620273954724e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PMS2 c.241G>A (p.Glu81Lys, p.E81K) variant has been reported in ClinVar predominantly as a variant of uncertain significance, with one benign submission and no expert panel classification.

2

This variant is present in population databases, including gnomAD v4.1 at AF 0.0000326 (52/1,593,986 alleles) and gnomAD v2.1 at AF 0.0000159 (4/250,820 alleles); the gnomAD v4.1 frequency is above the PMS2 PM2 threshold of <0.00002 and below the BS1 and BA1 thresholds.

3

For PMS2 missense variants, the HCI prior is the primary computational metric; this variant has an HCI prior probability of 0.0446, which is below the BP4 threshold of <0.11 and supports BP4_Supporting, while SpliceAI predicts no splice impact with a max delta score of 0.00.

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	Not met	This variant is a missense substitution, p.(Glu81Lys), and does not fall into the PMS2 VCEP loss-of-function categories for PVS1.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No evidence was identified that a different nucleotide change causing the same p.(Glu81Lys) amino acid substitution has already been established by the PMS2 VCEP as Pathogenic or Likely Pathogenic.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with the tumor and parental-testing requirements needed for PMS2 PS2 was identified.	cspec clinvar
PS3	Not assessed	No validated PMS2 functional assay result for p.(Glu81Lys) was identified that would support a damaging effect under the PMS2 VCEP functional framework.	cspec clinvar vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
PS4	N/A	PS4 is marked not applicable in the PMS2 VCEP framework.	cspec
PM1	N/A	PM1 is marked not applicable in the PMS2 VCEP framework.	cspec
PM2	Not met	This variant is present in gnomAD v4.1 at AF 0.0000326 (52/1,593,986 alleles), which is above the PMS2 PM2 threshold of <0.00002, so PM2_Supporting is not met.	cspec gnomad_v4
PM3	Not assessed	No phase-confirmed observation of this variant in trans with a pathogenic PMS2 variant in a constitutional mismatch repair deficiency context was identified.	cspec clinvar
PM4	N/A	PM4 is marked not applicable in the PMS2 VCEP framework.	cspec
PM5	Not met	No qualifying same-residue pathogenic or likely pathogenic missense comparator was identified for codon 81, and this variant also lacks the PP3 support required before applying PMS2 PM5.	cspec pm5_candidates hci_prior
PM6	N/A	PM6 is marked not applicable in the PMS2 VCEP framework.	cspec
PP1	Not assessed	No informative segregation data were identified for this variant, so the PMS2 PP1 Bayes likelihood ratio thresholds cannot be evaluated.	cspec clinvar
PP2	N/A	PP2 is marked not applicable in the PMS2 VCEP framework.	cspec
PP3	Not met	For PMS2 missense variants, the VCEP prioritizes the HCI prior. This variant has an HCI prior probability of 0.0446, which is below the PP3 thresholds of >0.68 for Supporting and >0.81 for Moderate, so PP3 is not met. SpliceAI also predicts no splice impact with a max delta score of 0.00.	cspec hci_prior spliceai revel bayesdel
PP4	Not assessed	No tumor microsatellite instability or immunohistochemistry evidence was identified to determine whether the clinical and tumor features meet the PMS2 PP4 thresholds.	cspec
PP5	N/A	PP5 is marked not applicable in the PMS2 VCEP framework.	cspec
BA1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 0.0000901, which is below the PMS2 BA1 threshold of 0.0028, so BA1 is not met.	cspec gnomad_v4
BS1	Not met	The gnomAD v4.1 highest observed population frequency is 0.000225 and the grpmax filtering allele frequency is 0.0000901, both below the PMS2 BS1 threshold of 0.00028, so BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No confirmed in-trans co-occurrence with a known pathogenic PMS2 variant in an individual meeting the PMS2 BS2 clinical requirements was identified.	cspec
BS3	Not assessed	No validated variant-specific functional study was identified showing retained PMS2 function or normal RNA behavior that would support BS3.	cspec clinvar vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
BS4	Not assessed	No informative family data were identified to show lack of segregation with disease, so BS4 cannot be evaluated.	cspec clinvar
BP1	N/A	BP1 is marked not applicable in the PMS2 VCEP framework.	cspec
BP2	N/A	BP2 is marked not applicable in the PMS2 VCEP framework.	cspec
BP3	N/A	BP3 is marked not applicable in the PMS2 VCEP framework.	cspec
BP4	Met	For PMS2 missense variants, the VCEP prioritizes the HCI prior. This variant has an HCI prior probability of 0.0446, which is below the BP4 threshold of <0.11, supporting benign computational evidence. SpliceAI also predicts no splice impact with a max delta score of 0.00.	cspec hci_prior spliceai revel bayesdel
BP5	Not assessed	No tumor phenotype data were identified to determine whether observed tumor features are inconsistent with a germline PMS2 explanation under the PMS2 BP5 rule.	cspec
BP6	N/A	BP6 is marked not applicable in the PMS2 VCEP framework.	cspec
BP7	N/A	This variant is a missense substitution rather than a synonymous or qualifying intronic change, so BP7 does not apply.	cspec

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