PMS2c.2380C>TUncertain significance

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Variant interpretation report

PMS2 c.2380C>T, p.(Pro794Ser)

NM_000535.7:c.2380C>T NP_000526.2:p.(Pro794Ser) 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.

Key facts

Evidence used: 1 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen PMS2 VCEP v2.0.0
Other laboratories (ClinVar): 12 Uncertain significance · 1 Benign
Pipeline record: 13 Jul 2026 · version 7.0.3

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): The variant is extremely rare in population databases, meeting the VCEP PM2_Supporting threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 3.67e-06 (5/1,604,584 alleles), well below the VCEP cutoff of <0.00002 (<1 in 50,000 alleles). One homozygote is observed in gnomAD v4.1, which may represent a technical artifact given the PMS2/PMS2CL pseudogene homology, but does not disqualify the allele frequency criterion.
PP3 (moderate): The HCI prior probability for pathogenicity (MAPP/PP2 Prior P score) for c.2380C>T (p.Pro794Ser) is 0.8253, exceeding the VCEP PP3_Moderate threshold of >0.81. This in silico predictor, calibrated for PMS2 missense variants, supports a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00), so the in silico evidence is limited to the amino acid substitution effect.

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 v2.0.0. 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: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PM2Supporting

PM2 · supporting

The variant is extremely rare in population databases, meeting the VCEP PM2_Supporting threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 3.67e-06 (5/1,604,584 alleles), well below the VCEP cutoff of <0.00002 (<1 in 50,000 alleles). One homozygote is observed in gnomAD v4.1, which may represent a technical artifact given the PMS2/PMS2CL pseudogene homology, but does not disqualify the allele frequency criterion.

PP3Moderate

PP3 · moderate

The HCI prior probability for pathogenicity (MAPP/PP2 Prior P score) for c.2380C>T (p.Pro794Ser) is 0.8253, exceeding the VCEP PP3_Moderate threshold of >0.81. This in silico predictor, calibrated for PMS2 missense variants, supports a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00), so the in silico evidence is limited to the amino acid substitution effect.

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 2.0.0 v2.0.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP3 moderate; 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.

gnomAD v4.1

gnomAD v2.1

Population frequency

5 / 1,604,584 alleles

gnomAD v4.1: 5 / 1,604,584 alleles. Recorded AF 3.11607e-06. Recorded homozygote count 1.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 8.07194e-06; MAF= 0.00081%, 2/247772 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.29012e-05; MAF= 0.00329%, 1/30394 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

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

Applied · PP3 → SpliceAI ↗

ClinVar submissions

13 reported laboratory submissions

12 Uncertain significance · 1 Benign. ClinVar API review status: criteria provided, conflicting classifications.

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 v2.0.0, with the data and sources behind each one.

27 criteria with recorded statuses: 2 met · 13 not met · 1 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000535.7:c.2380C>T (p.Pro794Ser) is a missense variant in exon 14 of PMS2.

This variant is extremely rare in population databases: gnomAD v4.1 grpmax filtering allele frequency is 3.67e-06 (5/1,604,584 alleles), meeting the VCEP PM2_Supporting threshold of <0.00002.

The HCI prior probability for pathogenicity is 0.8253, exceeding the VCEP PP3_Moderate threshold of >0.81, supporting a deleterious computational prediction.

No functional studies, segregation data, tumor pathology data, or de novo observations are available for this variant. The variant is absent from COSMIC and OncoKB reports no variant-specific functional evidence.

In ClinVar, this variant is classified as Uncertain Significance by 12 clinical laboratories and as Benign by 1 laboratory (ClinVar ID 220740), with no expert panel classification.

Applying the ClinGen InSiGHT PMS2 VCEP v2.0.0 combining criteria: PM2_Supporting (1 point) and PP3_Moderate (2 points) are met. These do not reach any pathogenic classification tier (requires ≥1 Strong or ≥3 Moderate for Likely Pathogenic, or ≥2 Supporting for Likely Benign). The variant remains a Variant of Uncertain Significance.

Met · 2

PM2 SupportingThe variant is extremely rare in population databases, meeting the VCEP PM2_Supporting threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 3.67e-06 (5/1,604,584 alleles), well below the VCEP cutoff of <0.00002 (<1 in 50,000 alleles). One homozygote is observed in gnomAD v4.1, which may represent a technical artifact given the PMS2/PMS2CL pseudogene homology, but does not disqualify the allele frequency criterion. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 3.67e-06 (< 0.00002 VCEP PM2_Supporting threshold)
gnomAD v2.1 AF = 8.07e-06 (2/247
772 alleles
0 homozygotes)
Absent from gnomAD-Canada v1.0

Sources

gnomad_v4 ↗

PP3 ModerateThe HCI prior probability for pathogenicity (MAPP/PP2 Prior P score) for c.2380C>T (p.Pro794Ser) is 0.8253, exceeding the VCEP PP3_Moderate threshold of >0.81. This in silico predictor, calibrated for PMS2 missense variants, supports a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00), so the in silico evidence is limited to the amino acid substitution effect. Details ▾Hide ▴

Evidence considered

HCI prior probability = 0.8253 (> 0.81 PP3_Moderate threshold)
MAPP score = 17.5
custom PP2 score = 0.999
SpliceAI max delta = 0.00 (no splicing impact)

Sources

hci_priorspliceai ↗

Not met · 13 · evaluated, threshold not reached

PS1 PS1 requires the same amino acid change (p.Pro794Ser) from a different underlying nucleotide change previously classified as Pathogenic or Likely Pathogenic by this VCEP. No alternative nucleotide substitution producing p.Pro794Ser is known or has been classified by the InSiGHT PMS2 VCEP. Details ▾Hide ▴

Evidence considered

No other nucleotide change encoding p.Pro794Ser has been reported or classified by the VCEP.

Sources

cspec ↗

PS2 PS2 requires de novo occurrence with confirmed maternity and paternity in a patient with MMR-deficient LS-spectrum tumor. No de novo observation has been reported for this variant. Details ▾Hide ▴

Evidence considered

No de novo data available.

Still missing

No de novo testing or reporting available for this variant.

PS3 PS3 requires variant-specific functional evidence from calibrated assays with defined odds of pathogenicity. The VCEP Functional-assay-SVI-documentation-MMR spreadsheet contains no entry for p.Pro794Ser. No functional data exists for this variant in the literature. Details ▾Hide ▴

Evidence considered

No functional assay data available for p.Pro794Ser in the VCEP functional assay calibration spreadsheet or the literature.

Still missing

No functional studies have assessed this variant.

PM5 PM5 requires a different missense change at the same amino acid residue (codon 794) previously classified as Pathogenic or Likely Pathogenic by this VCEP, with PP3 also being met. No other missense variant at codon 794 has been classified as P/LP by the InSiGHT PMS2 VCEP, and no comparator candidates were identified in ClinVar. Details ▾Hide ▴

Evidence considered

No established P/LP missense variants at PMS2 codon 794 identified by VCEP or in ClinVar.

Sources

cspec ↗pm5_candidates

PP1 PP1 requires co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio meeting VCEP thresholds. No co-segregation data are available for this variant. Details ▾Hide ▴

Evidence considered

No co-segregation data available.

Still missing

No segregation analysis has been performed for this variant.

PP4 PP4 requires MSI-H colorectal/endometrial tumors with loss of MMR protein expression consistent with PMS2. No tumor pathology data (MSI status, IHC) are available for carriers of this variant. Details ▾Hide ▴

Evidence considered

No tumor MSI/IHC data available for this variant.

Still missing

Tumor MSI and IHC data needed to evaluate PP4.

BA1 BA1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0028 (0.28%). The variant's grpmax FAF is 3.67e-06, far below this threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 3.67e-06 (< 0.0028 BA1 threshold).

Sources

gnomad_v4 ↗

BS1 BS1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.00028 and < 0.0028. The variant's grpmax FAF is 3.67e-06, below the BS1 lower bound. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 3.67e-06 (< 0.00028 BS1 threshold).

Sources

gnomad_v4 ↗

BS2 BS2 requires co-occurrence in trans with a known pathogenic PMS2 variant in a CRC patient after age 45 without CMMRD features. No such co-occurrence data are available. Details ▾Hide ▴

Evidence considered

No trans co-occurrence data available.

Still missing

No phase-confirmed co-occurrence data.

BS3 BS3 requires calibrated functional assays demonstrating a benign effect (odds of pathogenicity ≤ 0.05 for BS3_Strong, or proficient function per the MMR functional assay flowchart for BS3_Supporting). No functional data exist for p.Pro794Ser. Details ▾Hide ▴

Evidence considered

No functional assay data available for this variant.

Still missing

No functional studies have assessed this variant.

BS4 BS4 requires lack of co-segregation with disease in pedigrees meeting Bayes Likelihood Ratio thresholds. No segregation data are available. Details ▾Hide ▴

Evidence considered

No segregation data available.

Still missing

No segregation analysis has been performed.

BP4 BP4_Supporting for missense variants requires an HCI prior probability < 0.11. The HCI prior for c.2380C>T is 0.8253, which does not meet the BP4 threshold. REVEL score is 0.543 and BayesDel is 0.027, neither providing strong benign evidence. Details ▾Hide ▴

Evidence considered

HCI prior = 0.8253 (> 0.11 BP4 threshold
does not support benign)
REVEL = 0.543 (indeterminate)
BayesDel = 0.027 (does not clearly support benign)
SpliceAI max delta = 0.00 (no splicing impact)

Sources

hci_priorrevelbayesdelspliceai ↗

BP5 BP5 requires MSS colorectal/endometrial tumors and/or loss of MMR protein expression inconsistent with PMS2. No tumor pathology data are available. Details ▾Hide ▴

Evidence considered

No tumor MSS/IHC data available.

Still missing

Tumor pathology data needed to evaluate BP5.

Not assessed · 1 · no assessment recorded

PS5 PS5 is not included in the ClinGen InSiGHT PMS2 VCEP v2.0.0 specification and is not in the assessment list. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANM_000535.7:c.2380C>T is a missense substitution (p.Pro794Ser). The ClinGen InSiGHT PMS2 VCEP v2.0.0 PVS1 rules are restricted to nonsense/frameshift variants introducing a premature termination codon, canonical ±1,2 splice variants, initiation codon variants, and large genomic alterations. A missense variant does not qualify for any PVS1 strength tier. Details ▾Hide ▴

Evidence considered

Missense substitution p.Pro794Ser
not a null variant.

Evidence considered

Missense variant
BP7 restricted to synonymous and intronic variants.

Sources

cspec ↗

Identifiers

Gene: PMS2
Transcript: NM_000535.7
Coding (HGVS c.): NM_000535.7:c.2380C>T
Protein (HGVS p.): NP_000526.2:p.(Pro794Ser)
GRCh38: chr7:5977653 G>A
GRCh37: chr7:6017284 G>A
ClinVar: 220740

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…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in PMS2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 5 / 1,604,584 alleles AF 3.12e-06 · 1 homozygotes · FAF 3.67e-06

gnomAD v2.1 2 / 247,772 alleles AF 8.07e-06 · 0 homozygotes

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 3.1e-06 · 5 / 1,604,584 alleles · 1 hom · FAF 3.7e-06

South Asian2 / 90,516	2.2e-05
European (non-Finnish)3 / 1,173,772	2.6e-061 hom

0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 8.1e-06 · 2 / 247,772 alleles · 0 hom

South Asian1 / 30,394	3.3e-05
European (non-Finnish)1 / 111,322	9e-06

0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.11607e-06; MAF= 0.00031%, 5/1604584 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 2.20955e-05; MAF= 0.00221%, 2/90516 alleles, homozygotes = 0); grpmax FAF= 3.67e-06.

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: 0.543
BayesDel: 0.027

How the predictions were used

Evidence considered

HCI prior probability = 0.8253 (> 0.81 PP3_Moderate threshold)
MAPP score = 17.5
custom PP2 score = 0.999
SpliceAI max delta = 0.00 (no splicing impact)

Sources

hci_priorspliceai ↗

Evidence considered

HCI prior = 0.8253 (> 0.11 BP4 threshold
does not support benign)
REVEL = 0.543 (indeterminate)
BayesDel = 0.027 (does not clearly support benign)
SpliceAI max delta = 0.00 (no splicing impact)

Sources

hci_priorrevelbayesdelspliceai ↗

BP7 N/ABP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7. NM_000535.7:c.2380C>T is a missense variant (p.Pro794Ser) and does not qualify. Details ▾Hide ▴

Evidence considered

Missense variant
BP7 restricted to synonymous and intronic variants.

Sources

cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.543. BayesDel score = 0.0268987. HCI prior probability for pathogenicity = 0.8253. MAPP score = 17.5. Custom PP2 score = 0.999.

9 paper records 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

Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients.

van der Klift HM et al. · 2010

van der Klift et al. quantified sequence exchange events between PMS2 and PMS2CL and developed an RNA-based mutation detection strategy. The study identified 19 putative pathogenic PMS2 mutations. NM_000535.7:c.2380C>T (p.Pro794Ser) was not among the reported variants.
Does not name this variant
PMID 20186688 ↗
Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants.

Borràs E et al. · 2013

Borras et al. evaluated PMS2 variants in 13 Spanish Lynch syndrome patients with PMS2-negative tumors. Nine pathogenic variants and several VUS were characterized using in silico and in vitro functional analyses. NM_000535.7:c.2380C>T (p.Pro794Ser) was not among the variants studied.
Does not name this variant
PMID 23709753 ↗
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.

Richards S et al. · 2015

ACMG/AMP standards and guidelines for sequence variant interpretation. This is a general framework document; NM_000535.7:c.2380C>T is not discussed.
Does not name this variant
PMID 25741868 ↗
Lynch Syndrome.

Adam MP et al. · 1993

GeneReviews overview of Lynch Syndrome. Provides general clinical description, diagnosis, and management of Lynch syndrome. NM_000535.7:c.2380C>T is not discussed.
Does not name this variant
PMID 20301390 ↗
Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline.

NSGC/CGA-ICC joint practice guideline for identifying individuals at risk for Lynch syndrome. General clinical practice recommendations; does not discuss specific PMS2 variants.
Does not name this variant
PMID 22167527 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.

Green RC et al. · 2013

ACMG recommendations for reporting incidental findings in clinical exome and genome sequencing. Includes PMS2 in the list of reportable genes but does not discuss NM_000535.7:c.2380C>T.
Does not name this variant
PMID 23788249 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.

ACMG Board of Directors · 2015

ACMG policy statement on secondary findings in clinical genome-scale sequencing. Updates gene list recommendations; does not discuss NM_000535.7:c.2380C>T.
Does not name this variant
PMID 25356965 ↗
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

ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. General referral guidelines; does not discuss NM_000535.7:c.2380C>T.
Does not name this variant
PMID 25394175 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Sherloc refinement of ACMG-AMP variant classification criteria. General classification framework paper; NM_000535.7:c.2380C>T is not discussed.
Does not name this variant
PMID 28492532 ↗

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

gnomAD v4.1 5 / 1,604,584 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 12 Uncertain significance · 1 Benign 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

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (12 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 220740)

In silico

Functional

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.