Classification rationale

PM2 BP4 VUS

PMS2 c.706-13T>C unknown · exon 6i

PM2 Supporting: gnomAD v4.1 allele frequency 9.96589e-06 is below the VCEP threshold of 0.00002. BP4 Supporting: SpliceAI maximum delta score 0.009 is within the VCEP no-splicing-impact threshold of <=0.1.

PM2 + BP4 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000535.7 · variants mapped to exon structure

PMS2 NM_000535.7

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met at Supporting: gnomAD v4.1 allele frequency is 9.96589e-06, below the VCEP PM2 threshold of 0.00002.

gnomAD v4.1: total AF 9.96589e-06 from 15 alternate alleles among 1,505,134 alleles, with 0 homozygotes; the highest subpopulation AF was 1.71686e-05 in Admixed American individuals.The VCEP pilot-variant table was searched for NM_000535.7:c.706-13T>C, c.706-13T>C, and p.?; no matching row was found.The total gnomAD v4.1 allele frequency is below the VCEP PM2 cutoff of 0.00002.

gnomad_v4 ↗vcep_vcep_pilot_variants_mmr ↗cspec ↗

BP4 supporting Benign

Met at Supporting: SpliceAI maximum delta score 0.009 is within the VCEP BP4 no-impact threshold of <=0.1.

SpliceAI result for NM_000535.7:c.706-13T>C: DS_AG=0.007, DS_AL=0.001, DS_DG=0.009, DS_DL=0.000; maximum delta score=0.009.The VCEP BP4 intronic/synonymous path requires SpliceAI to predict no splicing impact with delta score <=0.1.HCI-PRIORS-PMS2.txt.txt was searched for c.706-13T>C, p.?, and p.?; no exact entry was found.

cspec ↗spliceai ↗vcep_hci_priors_pms2 ↗

Assessed · not applied · 3 not met · 11 not assessed

Pathogenic

PVS1 Not assessed: this non-canonical intronic variant has SpliceAI maximum delta 0.009 and lacks RNA evidence establishing a qualifying loss-of-function consequence.

PS1 Not assessed: no qualifying VCEP Pathogenic or Likely Pathogenic comparator was available for this non-canonical splice nucleotide.

PS2 Not assessed: no documented de novo observation, parental testing, confirmed parentage, or VCEP de novo-point assignment is available.

PS3 Not assessed: no variant-specific functional assay result, functional odds, or RNA assay outcome is available for PMS2 c.706-13T>C.

PM3 Not assessed: no affected proband, qualifying pathogenic PMS2 allele in trans, confirmed phase, or PM3 point total is documented.

PP1 Not assessed: no pedigree observations, informative meioses, or combined Bayes Likelihood Ratio are available for segregation analysis.

PP3 Not met: SpliceAI maximum delta score 0.009 is below the VCEP PP3 splice-defect threshold of 0.2.

PP4 Not assessed: no qualifying MSI-H tumor count or PMS2-consistent protein-loss result is available to compare with the VCEP PP4 rule.

Benign

BA1 Not met: gnomAD v4.1 Grpmax filtering allele frequency is 7.49e-06, below the VCEP BA1 threshold of 0.0028.

BS1 Not met: gnomAD v4.1 Grpmax filtering allele frequency is 7.49e-06, below the VCEP BS1 lower threshold of 0.00028.

BS2 Not assessed: no documented in-trans co-occurrence, confirmed phase, qualifying cancer age, or absence of CMMRD manifestations is available.

BS3 Not assessed: no variant-specific proficient-function result, functional odds, or NMD-inhibited RNA assay outcome is available for PMS2 c.706-13T>C.

BS4 Not assessed: no unaffected carrier observations, non-segregation data, informative meioses, or combined Bayes Likelihood Ratio are available.

BP5 Not assessed: no patient-specific MSS, MMR-protein, BRAF V600E, or MLH1-methylation tumor result is available for the BP5 rule.

N/A · 12 PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 9.96589e-06; MAF= 0.00100%, 15/1505134 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.71686e-05; MAF= 0.00172%, 1/58246 alleles, homozygotes = 0); grpmax FAF= 7.49e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.11467e-05; MAF= 0.00211%, 5/236444 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.75059e-05; MAF= 0.00375%, 4/106650 alleles, homozygotes = 0); grpmax FAF= 1.276e-05.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.001% · 15 / 1,505,134
0 hom · FAF 0.00075%

Admixed American 1 / 58,246	0.0017%
European (non-Finnish) 14 / 1,085,210	0.0013%

+ 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0021% · 5 / 236,444
0 hom · FAF 0.0013%

European (non-Finnish) 4 / 106,650	0.0038%
Admixed American 1 / 32,698	0.0031%

+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

0.011% · 2 / 18,418
0 hom · FAF 0.003%

⚠ LCR indel · split

European (non-Finnish)

2 / 11,738

0.017%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 182812)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 6 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

20301390 ↗ Lynch Syndrome. CLINVAR

23408351 ↗ Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. CLINVAR

24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR

31302137 ↗ Lynch Syndrome in Urologic Malignancies - What Does the Urologist Need to Know? CLINVAR

31479144 ↗ Medication Use to Reduce Risk of Breast Cancer: US Preventive Services Task Force Recommendation Statement. CLINVAR

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