Variant classification summary

NM_000535.7:c.1128A>C

PMS2 · NP_000526.2:p.(Pro376=) · NM_000535.7

GRCh37: chr7:6029447 T>G · GRCh38: chr7:5989816 T>G

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.(Pro376=)

gnomAD AF

7.504583377781968e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PMS2 c.1128A>C (p.Pro376=) variant has been observed once in somatic cancers in COSMIC and has been reported in ClinVar predominantly as likely benign or benign by multiple single-submitter clinical laboratories.

2

This variant is present in gnomAD v2.1 and v4.1 at low frequency and is absent from gnomAD-Canada; the v4.1 allele frequency is 7.50e-05 (121/1612348 alleles) with a highest observed population frequency of 9.93e-05 in non-Finnish Europeans, which is above the PMS2 PM2_Supporting cutoff of 0.00002 but below the BS1 and BA1 population thresholds.

3

SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, supporting BP4 and BP7 for this synonymous change.

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	N/A	This synonymous variant does not create a missense change and is not at a non-canonical splice nucleotide previously established as pathogenic or likely pathogenic, so the PMS2 PS1 rule does not apply.	cspec
PS2	Not assessed	No confirmed de novo data were identified, so PS2 cannot be assessed.	cspec
PP4	Not assessed	No tumor microsatellite instability or mismatch-repair immunohistochemistry data were identified for this variant, so PP4 cannot be assessed.	cspec
BP3	N/A	BP3 is not used in the PMS2 specification.	cspec
BP7	Met	This is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the benign splicing threshold of 0.1; this supports BP7.	cspec spliceai
BS2	Not assessed	No confirmed in trans co-occurrence with a pathogenic PMS2 variant in an older individual without features of constitutional mismatch repair deficiency was identified, so BS2 cannot be assessed.	cspec vcep_table_for_cmmrd_diagnosis
BP4	Met	For this synonymous variant, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is at or below the BP4 threshold of 0.1; this supports BP4.	cspec spliceai
PP1	Not assessed	No segregation data were identified, so PP1 cannot be assessed.	cspec
PS3	Not assessed	No validated functional or RNA assay evidence showing a damaging effect was identified for this variant, so PS3 cannot be assessed.	cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
BA1	Not met	The highest observed population frequency in gnomAD v4.1 is 9.93e-05 (0.00993%) in non-Finnish Europeans, which is below the BA1 threshold of 0.0028 (0.28%); BA1 is not met.	cspec gnomad_v4
PP2	N/A	PP2 is not used in the PMS2 specification.	cspec
BP1	N/A	BP1 is not used in the PMS2 specification.	cspec
BP6	N/A	BP6 is not used in the PMS2 specification.	cspec
PP5	N/A	PP5 is not used in the PMS2 specification.	cspec
BS4	Not assessed	No non-segregation data were identified, so BS4 cannot be assessed.	cspec
BS3	Not assessed	No validated functional or RNA assay evidence showing normal function or no mRNA aberration was identified for this variant, so BS3 cannot be assessed.	cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
PS4	N/A	PS4 is not used in the PMS2 specification.	cspec
PM4	N/A	PM4 is not used in the PMS2 specification.	cspec
BS1	Not met	The highest observed population frequency in gnomAD v4.1 is 9.93e-05 (0.00993%) in non-Finnish Europeans, which is below the BS1 range of 0.00028 to 0.0028; BS1 is not met.	cspec gnomad_v4
PP3	Not met	This synonymous variant does not meet the PMS2 missense HCI-prior rule, no HCI prior entry was available for c.1128A>C, and SpliceAI predicts no splice defect with a maximum delta score of 0.00, which is below the PP3 splice threshold of 0.2; PP3 is not met.	cspec spliceai vcep_hci_priors_pms2
PVS1	N/A	This variant is a synonymous substitution and does not fall into the PMS2 or generic PVS1 null-variant categories such as nonsense, frameshift, canonical +/-1 or 2 splice-site change, or a proven splice-aberrant transcript; PVS1 does not apply.	cspec pvs1_gene_context pvs1_variant_assessment
PM1	N/A	PM1 is not used in the PMS2 specification.	cspec
BP2	N/A	BP2 is not used in the PMS2 specification.	cspec
PM2	Not met	This variant is present in gnomAD v4.1 at AF 7.50e-05 (121/1612348 alleles), which is above the PMS2 PM2_Supporting threshold of 0.00002; PM2 is not met.	cspec gnomad_v4
BP5	Not assessed	No tumor evidence showing microsatellite-stable disease, retained mismatch-repair protein expression, or protein loss inconsistent with PMS2 was identified, so BP5 cannot be assessed.	cspec
PM6	N/A	PM6 is not used in the PMS2 specification.	cspec
PM3	Not assessed	No qualifying in trans observations for the recessive constitutional mismatch repair deficiency framework were identified, so PM3 cannot be assessed.	cspec vcep_table_for_cmmrd_diagnosis
PM5	N/A	The PMS2 PM5 rule is a classic same-residue missense rule, and this variant is not missense-like, so PM5 does not apply.	cspec pm5_candidates

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