Variant classification summary

NM_000535.7:c.830C>A

PMS2 · NP_000526.2:p.(Thr277Lys) · NM_000535.7

GRCh37: chr7:6035238 G>T · GRCh38: chr7:5995607 G>T

Gene: PMS2 Transcript: NM_000535.7

Final call

Benign

BA1 stand-alone benign BP4 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Thr277Lys)

gnomAD AF

0.00023863715251951247 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 (Stand-Alone) is met: the gnomAD v4.1 grpmax filtering allele frequency is 0.408%, exceeding the VCEP BA1 threshold of 0.28%, with one homozygote present in the database, excluding this variant as a cause of Lynch syndrome due to PMS2.

2

BP4 (Supporting) is met: the HCI prior probability for pathogenicity is 0.0013, below the BP4_Supporting threshold of <0.11, with multiple in silico predictors (REVEL 0.251, BayesDel -0.187, SpliceAI max delta 0.03) consistent with a benign computational profile.

3

This variant has been reported in ClinVar as Benign by 9 clinical laboratories, Likely Benign by 8 laboratories, and Uncertain Significance by 2 laboratories (ClinVar Variation ID: 135946).

4

PP3 is not met: the HCI prior of 0.0013 is far below the PP3_Supporting threshold of >0.68.

5

PM2_Supporting is not met: the gnomAD v4.1 allele frequency of 0.0239% exceeds the PM2 threshold of <0.002%.

Final determination: Rule17 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 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
PVS1	N/A	NM_000535.7:c.830C>A is a missense variant (p.Thr277Lys). PVS1 under the InSiGHT PMS2 VCEP v2.0.0 applies only to null variants (nonsense, frameshift, canonical ±1/2 splice sites, initiation codon, large genomic alterations) and is not applicable to missense substitutions.	cspec pvs1_variant_assessment
PS1	Not assessed	PS1 requires a different nucleotide change encoding the same amino acid (Thr277Lys) previously classified as Pathogenic by this VCEP. No such comparator variant was identified in the VCEP pilot variants spreadsheet or in ClinVar with a VCEP-level Pathogenic classification at this codon.
PS2	Not assessed	No de novo occurrence of NM_000535.7:c.830C>A has been reported in any published study or database. Exploratory literature and database search yielded no de novo observations.
PS3	Not assessed	No variant-specific functional assay data for NM_000535.7:c.830C>A (p.Thr277Lys) were confirmed from the available evidence. The exploratory search referenced Drost et al. (PMID:30504929) as a potential source, but variant-specific functional results were not retrieved. The VCEP functional assay documentation spreadsheet lists assay types but does not contain variant-level functional classifications.
PS4	N/A	PS4 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework.	cspec
PS5	N/A	PS5 is not defined in the InSiGHT PMS2 VCEP v2.0.0 framework. No VCEP rules exist for this criterion in this gene.	cspec
PM1	N/A	PM1 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework.	cspec
PM2	Not met	The VCEP PM2_Supporting rule requires gnomAD v4 allele frequency <0.00002 (<1 in 50,000 alleles). This variant has an allele frequency of 0.000239 (385/1,613,328 alleles) in gnomAD v4.1, exceeding the PM2 threshold by more than tenfold.	gnomad_v4
PM5	Not met	The VCEP PM5 rule requires PP3 to be supporting for the missense change, and a different missense at the same residue (Thr277) classified as Pathogenic or Likely Pathogenic by this VCEP. PP3 is not met (HCI prior 0.0013). Additionally, PM5 candidate search identified zero comparator candidates at this residue.	cspec pm5_candidates
PM6	N/A	PM6 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework.	cspec
PP1	Not assessed	No co-segregation data are available for this variant in families with Lynch syndrome or CMMRD. Exploratory search did not identify any published segregation analysis.
PP2	N/A	PP2 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework.	cspec
PP3	Not met	The VCEP PP3 rule uses the HCI prior probability for pathogenicity. PP3_Supporting requires HCI prior >0.68 and ≤0.81; PP3_Moderate requires >0.81. The HCI prior for c.830C>A (p.Thr277Lys) is 0.0013, well below both thresholds. SpliceAI predicts no splicing impact (max delta score 0.03), and REVEL (0.251) and BayesDel (-0.187) are consistent with a benign computational profile.	hci_prior revel bayesdel spliceai
PP4	Not assessed	No tumor MSI/IHC data are available for individuals carrying this variant. PP4 requires MSI-H tumors or loss of MMR protein expression consistent with the variant location in PMS2.
PP5	N/A	PP5 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework. This criterion is not used for PMS2 variant classification under this VCEP.	cspec
BA1	Met	The VCEP BA1 rule is met: gnomAD v4.1 grpmax filtering allele frequency is 0.00408 (0.408%), exceeding the BA1 threshold of ≥0.0028 (0.28%). One homozygote is present in gnomAD v4.1. The variant is enriched in the African/African American population (AF=0.448%) consistent with a population-specific polymorphism rather than a founder pathogenic variant; PMS2 pathogenic variants causing Lynch syndrome are incompatible with a homozygote in a general population database, as homozygosity would cause constitutional mismatch repair deficiency (CMMRD).	gnomad_v4 cspec
BS1	Not met	The VCEP BS1 threshold is ≥0.00028 (0.028%) and <0.0028 (0.28%). The gnomAD v4.1 grpmax FAF of 0.00408 (0.408%) exceeds the upper bound of the BS1 range, placing this variant in BA1 territory instead.	gnomad_v4 cspec
BS2	Not assessed	No data are available on co-occurrence of this variant in trans with a known pathogenic PMS2 variant in a patient with colorectal cancer after age 45 without CMMRD features.
BS3	Not assessed	No variant-specific functional assay data confirming normal MMR function for NM_000535.7:c.830C>A were identified. The VCEP functional assay documentation spreadsheet does not contain variant-level results. The exploratory search identified Drost et al. as a potential source, but variant-specific functional classification was not confirmed.
BS4	Not assessed	No family-based lack of co-segregation data are available for this variant. Exploratory search did not identify any published segregation or non-segregation analysis.
BP1	N/A	BP1 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework.	cspec
BP2	N/A	BP2 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework.	cspec
BP3	N/A	BP3 is trivially not applicable (in-frame indels in repetitive regions); this is a single nucleotide substitution. Also explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework.	cspec
BP4	Met	The VCEP BP4_Supporting rule is met: the HCI prior probability for c.830C>A (p.Thr277Lys) is 0.0013, which is below the BP4_Supporting threshold of <0.11. Multiple additional in silico predictors support a benign interpretation: REVEL score 0.251, BayesDel score -0.187, and SpliceAI max delta 0.03 (no predicted splicing impact).	hci_prior revel bayesdel spliceai cspec
BP5	Not assessed	No tumor data (MSS CRC/endometrial tumors, retained MMR protein expression, BRAF V600E, or MLH1 methylation) are available for carriers of this variant. BP5 requires tumor-based evidence of intact mismatch repair inconsistent with a PMS2 pathogenic variant.
BP6	N/A	BP6 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework.	cspec
BP7	N/A	BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. NM_000535.7:c.830C>A is a missense variant (p.Thr277Lys) and does not meet BP7 criteria.	cspec

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