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PMS2c.2515C>TUncertain significance
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Variant interpretation report

PMS2 c.2515C>T, p.(His839Tyr)

NM_000535.7:c.2515C>T NP_000526.2:p.(His839Tyr) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About PMS2

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is ClinGen PMS2 VCEP v2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Extremely rare in gnomAD v4.1 (1/739,742 alleles; AF=1.35e-06), below the VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles). Absent from gnomAD v2.1 and gnomAD-Canada.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 2.0 v2.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting; no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PMS2, an endonuclease involved in DNA repair, is altered in various cancers.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen PMS2 VCEP v2.0, with the data and sources behind each one.

29 criteria with recorded statuses: 1 met · 6 not met · 8 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000535.7:c.2515C>T (p.His839Tyr) is a missense variant in PMS2 exon 15. It is extremely rare in population databases (gnomAD v4.1: 1/739,742 alleles, AF=1.35e-06), meeting PM2_Supporting under the InSiGHT PMS2 VCEP specification.

In silico predictions are indeterminate: HCI prior probability is 0.514, which falls between the VCEP PP3 (>0.68) and BP4 (<0.11) thresholds. SpliceAI predicts no splicing impact (max delta=0.00).

No variant-specific functional data, segregation data, de novo observations, or tumor pathology data are available. This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (VariationID: 1792458, criteria provided, single submitter).

With only PM2_Supporting met and no benign criteria met, this variant is classified as Uncertain Significance under the InSiGHT PMS2 VCEP v2.0 framework.

Met · 1

PM2 SupportingExtremely rare in gnomAD v4.1 (1/739,742 alleles; AF=1.35e-06), below the VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles). Absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 1/739
  • 742 alleles
  • AF=1.35e-06
  • 0 homozygotes
Sources
gnomad_v4 ↗

Not met · 6 · evaluated, threshold not reached

PS1 No alternative nucleotide change encoding the same H839Y amino acid change has been established as Pathogenic by this VCEP. The reference codon is CAC; c.2515C>T is the only nucleotide substitution producing H839Y. Details ▾Hide ▴

No further detail was recorded.

PM5 No different missense change at codon 839 has been classified as Pathogenic or Likely Pathogenic by this VCEP. Other substitutions at this codon (c.2515C>A, p.H839N; c.2515C>G, p.H839D) have no established VCEP classification. Details ▾Hide ▴

No further detail was recorded.

PP3 HCI prior probability for c.2515C>T is 0.514, which does not meet VCEP PP3 thresholds (>0.68 for supporting, >0.81 for moderate). SpliceAI predicts no splicing impact (max delta score=0.00). REVEL score 0.632 is not used by the PMS2 VCEP for PP3. Details ▾Hide ▴
Evidence considered
  • HCI prior probability: 0.514 (threshold >0.68 for PP3_Supporting)
  • SpliceAI max delta: 0.00
Sources
hci_priorspliceai ↗
BA1 gnomAD v4 allele frequency (AF=1.35e-06) is far below the VCEP BA1 threshold of ≥0.0028 (0.28%). This variant is not a common population polymorphism. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF: 1.35e-06
Sources
gnomad_v4 ↗
BS1 gnomAD v4 allele frequency (AF=1.35e-06) is below the VCEP BS1 threshold of ≥0.00028 (0.028%). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF: 1.35e-06
Sources
gnomad_v4 ↗
BP4 HCI prior probability 0.514 exceeds the VCEP BP4 threshold of <0.11. Multiple in silico predictors do not suggest a benign effect (REVEL=0.632; BayesDel=0.022). SpliceAI predicts no splicing impact (max delta=0.00). Details ▾Hide ▴
Evidence considered
  • HCI prior: 0.514 (BP4 requires <0.11)
  • REVEL: 0.632
  • BayesDel: 0.022
  • SpliceAI max delta: 0.00
Sources
hci_priorrevelbayesdelspliceai ↗

Not assessed · 8 · no assessment recorded

PS2 No de novo data available for this variant. PS2 requires confirmed maternity and paternity in a proband with MMR-deficient LS spectrum tumor. Details ▾Hide ▴
Still missing
  • No de novo observations reported for this variant in any database or publication.
PS3 No variant-specific functional data available. OncoKB reports unknown oncogenic effect. No publications with functional evidence for NM_000535.7:c.2515C>T were identified. The VCEP functional assay documentation does not include this variant. Details ▾Hide ▴
Still missing
  • No functional assay data for this variant or for systematic range characterization including codon 839.
PP1 No co-segregation data available. PP1 requires combined Bayes Likelihood Ratio from pedigrees. Details ▾Hide ▴
Still missing
  • No segregation data or pedigree information available.
PP4 No patient phenotype, tumor MSI/IHC, or family history data available. PP4 requires MSI-H tumors or loss of MMR protein expression consistent with variant location. Details ▾Hide ▴
Still missing
  • No tumor pathology or phenotype data provided.
BS2 No co-occurrence or phase data available. BS2 requires observation in trans with a known pathogenic variant in a patient with CRC after age 45 without CMMRD features. Details ▾Hide ▴
Still missing
  • No co-occurrence/phase data available.
BS3 No variant-specific functional data demonstrating normal protein function. No calibrated functional assay data with odds favoring benign effect. Details ▾Hide ▴
Still missing
  • No functional assay data demonstrating normal/proficient MMR function.
BS4 No co-segregation data available. BS4 requires Bayes Likelihood Ratio from pedigrees demonstrating lack of segregation with disease. Details ▾Hide ▴
Still missing
  • No segregation data available.
BP5 No tumor data available. BP5 requires observation of MSS tumors without loss of MMR protein expression, or BRAF V600E/MLH1 methylation with MSI-H. Details ▾Hide ▴
Still missing
  • No tumor pathology data available.
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (NP_000526.2:p.His839Tyr); PVS1 applies only to null variants (nonsense, frameshift, canonical ±1/2 splice, initiation codon). Not applicable to missense substitutions. Details ▾Hide ▴

No further detail was recorded.

PS4 VCEPPS4 is marked Not Applicable by the InSiGHT PMS2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PM1 VCEPPM1 is marked Not Applicable by the InSiGHT PMS2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ARecessive disorder data not applicable for PMS2; Lynch syndrome is autosomal dominant. Details ▾Hide ▴

No further detail was recorded.

PM4 VCEPMissense variant; PM4 applies to protein length changes (in-frame deletions/insertions, stop-loss). Not applicable to missense substitutions. Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPPM6 is marked Not Applicable by the InSiGHT PMS2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPPP2 is marked Not Applicable by the InSiGHT PMS2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PP5 VCEPPP5 is marked Not Applicable by the InSiGHT PMS2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPBP1 is marked Not Applicable by the InSiGHT PMS2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

BP2 VCEPBP2 is marked Not Applicable by the InSiGHT PMS2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

BP3 VCEPMissense variant; BP3 applies to in-frame deletions/insertions in repetitive regions. Not applicable to missense substitutions. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is marked Not Applicable by the InSiGHT PMS2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AMissense variant; BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. Not applicable to missense substitutions. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not included in the InSiGHT PMS2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
PMS2
Transcript
NM_000535.7
Coding (HGVS c.)
NM_000535.7:c.2515C>T
Protein (HGVS p.)
NP_000526.2:p.(His839Tyr)
GRCh38
chr7:5973473 G>A
GRCh37
chr7:6013104 G>A
ClinVar
1792458

Gene diagram

Every interpreted variant in PMS2, mapped onto the exon structure of NM_000535.7. Select a row to find it on the plot.

PMS2NM_000535.7
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 739,742 alleles AF 1.35e-06 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.4e-06 · 1 / 739,742 alleles · 0 hom
Remaining individuals1 / 33,176 3e-05
0 alternate alleles recorded in 9 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.35182e-06; MAF= 0.00014%, 1/739742 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.01423e-05; MAF= 0.00301%, 1/33176 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.632
BayesDel
0.022

How the predictions were used

PP3 HCI prior probability for c.2515C>T is 0.514, which does not meet VCEP PP3 thresholds (>0.68 for supporting, >0.81 for moderate). SpliceAI predicts no splicing impact (max delta score=0.00). REVEL score 0.632 is not used by the PMS2 VCEP for PP3. Details ▾Hide ▴
Evidence considered
  • HCI prior probability: 0.514 (threshold >0.68 for PP3_Supporting)
  • SpliceAI max delta: 0.00
Sources
hci_priorspliceai ↗
BP4 HCI prior probability 0.514 exceeds the VCEP BP4 threshold of <0.11. Multiple in silico predictors do not suggest a benign effect (REVEL=0.632; BayesDel=0.022). SpliceAI predicts no splicing impact (max delta=0.00). Details ▾Hide ▴
Evidence considered
  • HCI prior: 0.514 (BP4 requires <0.11)
  • REVEL: 0.632
  • BayesDel: 0.022
  • SpliceAI max delta: 0.00
Sources
hci_priorrevelbayesdelspliceai ↗
BP7 N/AMissense variant; BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. Not applicable to missense substitutions. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.632. BayesDel score = 0.0217699. HCI prior probability for pathogenicity = 0.514. MAPP score = 10.36. Custom PP2 score = 0.927.

1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    Practice guideline from ACMG and NSGC outlining referral indications for cancer predisposition assessment. Discusses hereditary cancer syndromes including Lynch syndrome at the gene level. NM_000535.7:c.2515C>T was not identified in this paper.
    Does not name this variant
    PMID 25394175 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 739,742 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 2 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.35182e-06; MAF= 0.00014%, 1/739742 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.01423e-05; MAF= 0.00301%, 1/33176 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1792458)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.632. BayesDel score = 0.0217699. HCI prior probability for pathogenicity = 0.514. MAPP score = 10.36. Custom PP2 score = 0.927.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PMS2, an endonuclease involved in DNA repair, is altered in various cancers.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.