Analysis in progress
Initialising…
0%
complete
This report is still being assembled — sections appear as each stage finishes. It isn't final yet.
PMS2
Final classification
Likely Benign
PMS2 c.705+24C>T · p.?
PMS2

NM_000535.7:c.705+24C>T is an intronic variant in PMS2 located at position +24 of intron 6, outside the canonical splice consensus region.

Gene
PMS2
Transcript
NM_000535.7
HGVS · transcript:coding
NM_000535.7:c.705+24C>T
Consequence
N/A
GRCh38
chr7:5999084 G>A
GRCh37
chr7:6038715 G>A
Basis 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: matched Rule19 (Benign.Supporting >=2) with applied criteria: PM2 supporting, BP4 supporting benign, BP7 supporting benign; maps to Likely Benign.
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: matched Rule19 (Benign.Supporting >=2) with applied criteria: PM2 supporting, BP4 supporting benign, BP7 supporting benign; maps to Likely Benign.
Classification rationale
PM2 BP4BP7 Likely Benign
PMS2 c.705+24C>T

NM_000535.7:c.705+24C>T is an intronic variant in PMS2 located at position +24 of intron 6, outside the canonical splice consensus region.1 This variant is present in gnomAD v4.1 at an extremely low overall allele frequency of 1.18e-05 (19/1,610,524 alleles, no homozygotes), meeting PM2_Supporting per InSiGHT PMS2 VCEP criteria (allele frequency <0.00002).2 SpliceAI predicts no splicing impact with a maximum delta score of 0.04, meeting BP4_Supporting per the InSiGHT PMS2 VCEP (delta ≤0.1 for intronic variants).3 The variant is at intronic position +24, which is beyond the +7 canonical splice donor boundary, meeting BP7_Supporting per the InSiGHT PMS2 VCEP (intronic variants at or beyond -21/+7).4 The variant is absent from ClinVar and no publications were identified that mention NM_000535.7:c.705+24C>T.5 The variant has been observed in COSMIC (COSV113734575, n=2 somatic occurrences), but this does not constitute germline evidence of pathogenicity. Criteria met: PM2_Supporting (extremely rare in population databases). Benign criteria met: BP4_Supporting (SpliceAI predicts no splice impact), BP7_Supporting (intronic variant beyond canonical splice region).6 Per InSiGHT PMS2 VCEP v2.0.0 combination Rule 31, the co-occurrence of pathogenic supporting evidence (PM2) and benign supporting evidence (BP4, BP7) results in Uncertain Significance — Conflicting Evidence. While the variant also satisfies Rule 19 (≥2 benign supporting criteria for Likely Benign), the presence of pathogenic supporting evidence triggers the conflicting evidence rule.7

PM2 + BP4 + BP7 Likely Benign
Gene diagram · NM_000535.7 · variants mapped to exon structure
PMS2 NM_000535.7
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 12 assessed
Applied · 3
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
NM_000535.7:c.705+24C>T has an overall allele frequency of 1.18e-05 (19/1,610,524 alleles) in gnomAD v4.1, which is below the VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD-Canada v1.0. Per the InSiGHT PMS2 VCEP v2.0.0, this meets PM2_Supporting.
gnomAD v4.1 total AF = 1.18e-05 (19/1610524 alleles)
BP4 supporting Benign
NM_000535.7:c.705+24C>T is an intronic variant. SpliceAI predicts no splicing impact with a maximum delta score of 0.04, which is ≤0.1. Per the InSiGHT PMS2 VCEP v2.0.0, intronic variants with SpliceAI delta ≤0.1 meet BP4_Supporting (Walker et al. 2023).
SpliceAI max delta = 0.04below BP4 threshold of ≤0.1 for intronic variants.
BP7 supporting Benign
NM_000535.7:c.705+24C>T is an intronic variant located at position +24 in intron 6 of PMS2, which is beyond the +7 canonical splice donor boundary. Per the InSiGHT PMS2 VCEP v2.0.0, intronic variants at or beyond -21/+7 meet BP7_Supporting. This criterion may be combined with BP4 as noted in the VCEP rule.
Intronic variant at position +24beyond the +7 canonical splice donor boundary.
Assessed · not applied
Pathogenic
PS1 PS1 requires either a predicted missense substitution encoding the same amino acid change as a previously established pathogenic variant, or a variant affecting the same non-canonical splice nucleotide as a confirmed pathogenic splice variant with similar or worse SpliceAI prediction.
PS2 No de novo observations are available for NM_000535.7:c.705+24C>T.
PS3 No functional assay data are available for NM_000535.7:c.705+24C>T.
PP1 No co-segregation data are available for NM_000535.7:c.705+24C>T.
PP3 PP3 in the InSiGHT PMS2 VCEP requires either an HCI prior score >0.68 for missense variants or a SpliceAI delta score ≥0.2 for non-canonical splice variants.
PP4 No tumor phenotype data are available for NM_000535.7:c.705+24C>T.
Benign
BA1 The gnomAD v4.1 grpmax filtering allele frequency for NM_000535.7:c.705+24C>T is 3.59e-05 (0.00359%), which is far below the VCEP BA1 threshold of ≥0.0028 (0.28%).
BS1 The gnomAD v4.1 grpmax filtering allele frequency for NM_000535.7:c.705+24C>T is 3.59e-05 (0.00359%), which is below the VCEP BS1 threshold range of ≥0.00028 and <0.0028 (0.028%-0.28%).
BS2 BS2 requires co-occurrence in trans with a known pathogenic PMS2 variant in a patient with colorectal cancer after age 45 without CMMRD features.
BS3 BS3 requires calibrated functional assays showing benign functional odds (≤0.05 for Strong, >0.05 & ≤0.48 for Supporting), or for intronic variants, laboratory assays demonstrating no associated mRNA aberration with NMD inhibition.
BS4 No co-segregation data are available for NM_000535.7:c.705+24C>T.
BP5 No tumor phenotype data are available for NM_000535.7:c.705+24C>T.
N/A · 13 PVS1 · PS4 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.17974e-05; MAF= 0.00118%, 19/1610524 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000167616; MAF= 0.01676%, 1/5966 alleles, homozygotes = 0); grpmax FAF= 3.59e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.95336e-06; MAF= 0.00080%, 2/251466 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0012% · 19 / 1,610,524
0 hom · FAF 0.0036%
Middle Eastern
1 / 5,966
0.017%
South Asian
7 / 91,000
0.0077%
Admixed American
2 / 59,982
0.0033%
Remaining individuals
1 / 62,368
0.0016%
African/African American
1 / 74,914
0.0013%
European (non-Finnish)
7 / 1,176,960
0.00059%
+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0008% · 2 / 251,466
0 hom
South Asian
1 / 30,616
0.0033%
Admixed American
1 / 34,590
0.0029%
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV113734575, n = 2 times).
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