LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-06-14
Case ID: NM_000535.7_c.2566C_T_20260614_175207
Framework: ACMG/AMP 2015
Variant classification summary

NM_000535.7:c.2566C>T

PMS2  · NP_000526.2:p.(Leu856=)  · NM_000535.7
GRCh37: chr7:6013053 G>A  ·  GRCh38: chr7:5973422 G>A
Gene: PMS2 Transcript: NM_000535.7
Final call
Likely Benign
PM2 supporting BP4 supporting benign BP7 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
PMS2
Transcript
NM_000535.7
Protein
NP_000526.2:p.(Leu856=)
gnomAD AF
5.057022991249328e-06 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_000535.7:c.2566C>T (p.Leu856=) is a synonymous variant in exon 15 of PMS2. It is extremely rare in population databases, with an allele frequency of 5.057e-06 in gnomAD v4.1 (5/988,724 alleles, no homozygotes) and absent from gnomAD v2.1, satisfying PM2_Supporting per PMS2 VCEP v2.0.0.
2
SpliceAI predicts no splicing impact for this variant (max delta = 0.00), satisfying BP4_Supporting per PMS2 VCEP v2.0.0 for synonymous variants.
3
The variant is a synonymous substitution located at c.2566 in exon 15, +120 nucleotides from the splice acceptor site, well beyond the +7 position defined by the BP7 rule. BP7_Supporting is met per PMS2 VCEP v2.0.0.
4
PVS1, PS1, and PM5 are not applicable as this is a synonymous variant producing no amino acid change. PS4, PM1, PM6, PP2, PP5, BP1, BP2, and BP6 are not applicable per the PMS2 VCEP v2.0.0 specifications.
5
No de novo observations (PS2), functional studies (PS3, BS3), cosegregation data (PP1, BS4), trans co-occurrence data (BS2), tumor pathology data (PP4, BP5), or computational evidence supporting pathogenicity (PP3) were identified for this variant.
6
This variant has been reported in ClinVar as Likely benign by four clinical laboratories and Benign by one clinical laboratory (ClinVar ID 701564). In ClinVar, submissions cited methodology papers without variant-specific clinical evidence.
7
Under the PMS2 VCEP v2.0.0 combination rules, the presence of two benign supporting criteria (BP4_Supporting, BP7_Supporting) satisfies Rule19 (>=2 Benign.Supporting -> Likely Benign). PM2_Supporting is also met but does not alter the classification under the VCEP rule hierarchy.
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
PVS1 N/A PVS1 is not applicable to synonymous variants. NM_000535.7:c.2566C>T is a synonymous substitution (p.Leu856=) and does not introduce a premature termination codon, disrupt the initiation codon, or affect a canonical splice site. Per PMS2 VCEP v2.0.0, PVS1 applies only to null variants (nonsense, frameshift, canonical splice, or large genomic alterations).
cspec pvs1_gene_context pvs1_variant_assessment
PS1 N/A PS1 requires a predicted missense substitution that encodes the same amino acid change as a previously established Pathogenic variant. NM_000535.7:c.2566C>T is a synonymous variant with no amino acid change; therefore PS1 is not applicable.
cspec
PS2 Not met No de novo occurrences of NM_000535.7:c.2566C>T were identified in the literature or curated de novo databases. Per PMS2 VCEP v2.0.0, PS2 requires documented de novo observation with assigned point values.
PS3 Not met No well-established functional studies demonstrating a damaging effect of NM_000535.7:c.2566C>T on PMS2 protein function or splicing were identified. The PMS2 VCEP functional assay documentation spreadsheet does not include this variant. As a synonymous variant, functional impact would require evidence of aberrant splicing, which SpliceAI does not predict (max delta = 0.00).
spliceai
PS4 N/A PS4 is listed as Not Applicable in the PMS2 VCEP v2.0.0 specifications.
cspec
PS5 N/A PS5 applies to variants with the same amino acid change as a previously established pathogenic variant. NM_000535.7:c.2566C>T is a synonymous variant (p.Leu856=) with no amino acid change; therefore PS5 is not applicable.
PM1 N/A PM1 is listed as Not Applicable in the PMS2 VCEP v2.0.0 specifications.
cspec
PM2 Met NM_000535.7:c.2566C>T is extremely rare in population databases. The variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 5.057e-06 (5/988,724 alleles, no homozygotes), which is below the PMS2 VCEP v2.0.0 PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). The grpmax filtering allele frequency is 1.39e-06.
gnomad_v2 gnomad_v4 cspec
PM5 N/A PM5 requires a missense change at an amino acid residue where a different missense change was classified as Pathogenic. NM_000535.7:c.2566C>T is a synonymous variant (p.Leu856=) and does not alter the amino acid; therefore PM5 is not applicable.
cspec pm5_candidates
PM6 N/A PM6 is listed as Not Applicable in the PMS2 VCEP v2.0.0 specifications.
cspec
PP1 Not met No cosegregation data in affected family members were identified for NM_000535.7:c.2566C>T. Per PMS2 VCEP v2.0.0, PP1 requires combined Bayes Likelihood Ratio exceeding defined thresholds in pedigrees with disease.
PP2 N/A PP2 is listed as Not Applicable in the PMS2 VCEP v2.0.0 specifications.
cspec
PP3 Not met PP3 per PMS2 VCEP v2.0.0 requires either a missense variant with HCI prior probability >0.68, or a predicted splice defect for non-canonical splicing nucleotides with SpliceAI delta >= 0.2. NM_000535.7:c.2566C>T is a synonymous variant not present in the HCI prior lookup table (which is populated only for missense substitutions), and SpliceAI predicts no splicing impact (max delta = 0.00). Neither PP3 branch is satisfied.
cspec spliceai
PP4 Not met No CRC/endometrial MSI-H tumors or loss of MMR protein expression consistent with this variant location were identified for NM_000535.7:c.2566C>T. Per PMS2 VCEP v2.0.0, PP4 requires documented MSI-H tumors and/or MMR protein expression loss.
PP5 N/A PP5 is listed as Not Applicable in the PMS2 VCEP v2.0.0 specifications.
cspec
BA1 Not met BA1 per PMS2 VCEP v2.0.0 requires gnomAD v4 grpmax filtering allele frequency >= 0.0028 (0.28%). The observed grpmax FAF for NM_000535.7:c.2566C>T is 1.39e-06, well below the BA1 threshold.
gnomad_v4 cspec
BS1 Not met BS1 per PMS2 VCEP v2.0.0 requires gnomAD v4 grpmax filtering allele frequency >= 0.00028 and < 0.0028. The observed grpmax FAF for NM_000535.7:c.2566C>T is 1.39e-06, which is below the lower BS1 bound of 0.00028.
gnomad_v4 cspec
BS2 Not met No reports of NM_000535.7:c.2566C>T observed in trans with a known pathogenic PMS2 variant in a patient with colorectal cancer after age 45 and no evidence of CMMRD were identified. Per PMS2 VCEP v2.0.0, BS2 requires documented co-occurrence in trans with confirmation of phase.
BS3 Not met No well-established functional studies demonstrating no damaging effect of NM_000535.7:c.2566C>T were identified. Per PMS2 VCEP v2.0.0, BS3 requires calibrated functional assays with odds for pathogenicity <= 0.05, or synonymous variants with no mRNA aberration demonstrated by laboratory assay. No such studies have been published for this variant. ClinVar classification as Likely benign is not a functional assay.
cspec
BS4 Not met No dedicated segregation studies demonstrating lack of cosegregation with disease were identified for NM_000535.7:c.2566C>T. Per PMS2 VCEP v2.0.0, BS4 requires combined Bayes Likelihood Ratio < 0.05 from pedigree analysis.
BP1 N/A BP1 is listed as Not Applicable in the PMS2 VCEP v2.0.0 specifications.
cspec
BP2 N/A BP2 is listed as Not Applicable in the PMS2 VCEP v2.0.0 specifications.
cspec
BP4 Met NM_000535.7:c.2566C>T is a synonymous variant and SpliceAI predicts no splicing impact (max delta score = 0.00), which satisfies the PMS2 VCEP v2.0.0 BP4_Supporting rule for intronic and synonymous variants (SpliceAI delta score <= 0.1). The HCI prior branch of BP4 does not apply as this is not a missense variant.
cspec spliceai
BP5 Not met No tumor pathology data (MSS tumors, BRAF V600E, MLH1 methylation) were identified for NM_000535.7:c.2566C>T. Per PMS2 VCEP v2.0.0, BP5 requires documented CRC/endometrial tumors with MSS and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation findings.
BP6 N/A BP6 is listed as Not Applicable in the PMS2 VCEP v2.0.0 specifications.
cspec
BP7 Met NM_000535.7:c.2566C>T is a synonymous (silent) variant located in exon 15 of PMS2 (c.2446-c.*2474) at position c.2566, which is +120 nucleotides downstream of the splice acceptor site. This is beyond the +7 position from the 3' exon boundary, satisfying the PMS2 VCEP v2.0.0 BP7 rule for synonymous variants at or beyond -21/+7 (5'/3' exonic). The variant does not lie within the critical splice consensus region.
cspec spliceai
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