About PMS2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PMS2 c.1128A>C, p.(Pro376=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
For this synonymous variant, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is at or below the BP4 threshold of 0.1; this supports BP4.
BP7Supporting
BP7 · supporting
This is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the benign splicing threshold of 0.1; this supports BP7.
Recorded classification: 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: BP7 supporting, BP4 supporting; maps to Likely Benign.
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
121 / 1,612,348 alleles
gnomAD v4.1: 121 / 1,612,348 alleles. Recorded AF 7.50458e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.58175e-05; MAF= 0.00358%, 9/251274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.91431e-05; MAF= 0.00791%, 9/113718 alleles, homozygotes = 0); grpmax FAF= 4.115e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
9 reported laboratory submissions
5 Likely benign · 2 Likely Benign · 1 Benign · 1 likely benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV56224632, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PMS2 VCEP v2.0.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 9 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The PMS2 c.1128A>C (p.Pro376=) variant has been observed once in somatic cancers in COSMIC and has been reported in ClinVar predominantly as likely benign or benign by multiple single-submitter clinical laboratories.
This variant is present in gnomAD v2.1 and v4.1 at low frequency and is absent from gnomAD-Canada; the v4.1 allele frequency is 7.50e-05 (121/1612348 alleles) with a highest observed population frequency of 9.93e-05 in non-Finnish Europeans, which is above the PMS2 PM2_Supporting cutoff of 0.00002 but below the BS1 and BA1 population thresholds.
SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, supporting BP4 and BP7 for this synonymous change.
No criteria match.
Met · 2
BP4 SupportingFor this synonymous variant, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is at or below the BP4 threshold of 0.1; this supports BP4. Details ▾Hide ▴
Rule
Synonymous or intronic variant with SpliceAI delta score <=0.1
Evidence considered
- SpliceAI max delta score 0.00.
Sources
BP7 SupportingThis is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the benign splicing threshold of 0.1; this supports BP7. Details ▾Hide ▴
Rule
Synonymous or qualifying intronic variant; may satisfy BP7 with no predicted splice impact
Evidence considered
- Synonymous change p.(Pro376=).
- SpliceAI max delta score 0.00.
Sources
Not met · 4 · evaluated, threshold not reached
PM2 This variant is present in gnomAD v4.1 at AF 7.50e-05 (121/1612348 alleles), which is above the PMS2 PM2_Supporting threshold of 0.00002; PM2 is not met. Details ▾Hide ▴
Rule
Absent or extremely rare in gnomAD v4 with AF <0.00002
Evidence considered
- gnomAD v4.1 total AF 7.50458e-05
- 121/1612348 alleles.
Sources
PP3 This synonymous variant does not meet the PMS2 missense HCI-prior rule, no HCI prior entry was available for c.1128A>C, and SpliceAI predicts no splice defect with a maximum delta score of 0.00, which is below the PP3 splice threshold of 0.2; PP3 is not met. Details ▾Hide ▴
Rule
Missense HCI prior >0.68 or non-canonical splice variant with SpliceAI >=0.2
Evidence considered
- No HCI prior entry for c.1128A>C.
- SpliceAI max delta score 0.00.
Sources
BA1 The highest observed population frequency in gnomAD v4.1 is 9.93e-05 (0.00993%) in non-Finnish Europeans, which is below the BA1 threshold of 0.0028 (0.28%); BA1 is not met. Details ▾Hide ▴
Rule
GnomAD v4 grpmax filtering allele frequency >=0.0028
Evidence considered
- gnomAD v4.1 highest observed population AF 9.93e-05.
Sources
BS1 The highest observed population frequency in gnomAD v4.1 is 9.93e-05 (0.00993%) in non-Finnish Europeans, which is below the BS1 range of 0.00028 to 0.0028; BS1 is not met. Details ▾Hide ▴
Rule
GnomAD v4 grpmax filtering allele frequency >=0.00028 and <0.0028
Evidence considered
- gnomAD v4.1 highest observed population AF 9.93e-05.
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo data were identified, so PS2 cannot be assessed. Details ▾Hide ▴
Rule
PMS2 VCEP de novo point-based rule
Evidence considered
- No de novo evidence identified.
Still missing
- Maternity/paternity confirmation and proband-level tumor context were not available.
Sources
PS3 No validated functional or RNA assay evidence showing a damaging effect was identified for this variant, so PS3 cannot be assessed. Details ▾Hide ▴
Rule
PMS2 VCEP functional evidence rule
Evidence considered
- No qualifying damaging functional evidence identified.
Still missing
- Variant-specific calibrated functional or constitutional RNA studies were not available.
Sources
PM3 No qualifying in trans observations for the recessive constitutional mismatch repair deficiency framework were identified, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
PMS2 VCEP recessive point-based rule
Evidence considered
- No qualifying PM3 evidence identified.
Still missing
- Phase-confirmed trans observations and phenotype details were not available.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
PP1 No segregation data were identified, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
PMS2 VCEP segregation likelihood-ratio rule
Evidence considered
- No segregation evidence identified.
Still missing
- Family segregation data with calculable Bayes likelihood ratio were not available.
Sources
PP4 No tumor microsatellite instability or mismatch-repair immunohistochemistry data were identified for this variant, so PP4 cannot be assessed. Details ▾Hide ▴
Rule
PMS2 VCEP tumor phenotype rule
Evidence considered
- No phenotype-specific tumor data identified.
Still missing
- CRC/endometrial MSI or IHC evidence consistent with PMS2 loss was not available.
Sources
BS2 No confirmed in trans co-occurrence with a pathogenic PMS2 variant in an older individual without features of constitutional mismatch repair deficiency was identified, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
PMS2 VCEP in trans co-occurrence rule
Evidence considered
- No qualifying in trans co-occurrence data identified.
Still missing
- Phase-confirmed co-occurrence and clinical context for CMMRD exclusion were not available.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
BS3 No validated functional or RNA assay evidence showing normal function or no mRNA aberration was identified for this variant, so BS3 cannot be assessed. Details ▾Hide ▴
Rule
PMS2 VCEP benign functional evidence rule
Evidence considered
- No qualifying benign functional evidence identified.
Still missing
- Variant-specific benign functional or constitutional RNA studies were not available.
Sources
BS4 No non-segregation data were identified, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
PMS2 VCEP non-segregation likelihood-ratio rule
Evidence considered
- No qualifying non-segregation evidence identified.
Still missing
- Family segregation data showing lack of co-segregation were not available.
Sources
BP5 No tumor evidence showing microsatellite-stable disease, retained mismatch-repair protein expression, or protein loss inconsistent with PMS2 was identified, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
PMS2 VCEP contradictory tumor phenotype rule
Evidence considered
- No qualifying contradictory tumor data identified.
Still missing
- Contradictory tumor phenotype data were not available.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a synonymous substitution and does not fall into the PMS2 or generic PVS1 null-variant categories such as nonsense, frameshift, canonical +/-1 or 2 splice-site change, or a proven splice-aberrant transcript; PVS1 does not apply. Details ▾Hide ▴
Rule
PMS2 VCEP PVS1 loss-of-function rule
Evidence considered
- PVS1 gene gate eligible for PMS2 in general.
- Variant-specific assessment placed this change outside default PVS1 buckets.
Sources
PS1 N/AThis synonymous variant does not create a missense change and is not at a non-canonical splice nucleotide previously established as pathogenic or likely pathogenic, so the PMS2 PS1 rule does not apply. Details ▾Hide ▴
Rule
PMS2 VCEP PS1 same amino-acid-change or same non-canonical splice-nucleotide rule
Evidence considered
- PMS2 c.1128A>C results in p.(Pro376=)
- not a missense or non-canonical splice-site match for PS1.
Sources
PS4 VCEPPS4 is not used in the PMS2 specification. Details ▾Hide ▴
VCEP rule
Not applicable in PMS2 VCEP
Evidence considered
- Criterion marked not applicable in PMS2 specification.
Sources
PM1 VCEPPM1 is not used in the PMS2 specification. Details ▾Hide ▴
VCEP rule
Not applicable in PMS2 VCEP
Evidence considered
- Criterion marked not applicable in PMS2 specification.
Sources
PM4 VCEPPM4 is not used in the PMS2 specification. Details ▾Hide ▴
VCEP rule
Not applicable in PMS2 VCEP
Evidence considered
- Criterion marked not applicable in PMS2 specification.
Sources
PM5 N/AThe PMS2 PM5 rule is a classic same-residue missense rule, and this variant is not missense-like, so PM5 does not apply. Details ▾Hide ▴
Rule
PMS2 VCEP same-residue missense rule
Evidence considered
- PM5 candidate review marked the variant as not eligible for classic same-residue missense PM5.
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is not used in the PMS2 specification. Details ▾Hide ▴
VCEP rule
Not applicable in PMS2 VCEP
Evidence considered
- Criterion marked not applicable in PMS2 specification.
Sources
PP2 VCEPPP2 is not used in the PMS2 specification. Details ▾Hide ▴
VCEP rule
Not applicable in PMS2 VCEP
Evidence considered
- Criterion marked not applicable in PMS2 specification.
Sources
PP5 VCEPPP5 is not used in the PMS2 specification. Details ▾Hide ▴
VCEP rule
Not applicable in PMS2 VCEP
Evidence considered
- Criterion marked not applicable in PMS2 specification.
Sources
BP1 VCEPBP1 is not used in the PMS2 specification. Details ▾Hide ▴
VCEP rule
Not applicable in PMS2 VCEP
Evidence considered
- Criterion marked not applicable in PMS2 specification.
Sources
BP2 VCEPBP2 is not used in the PMS2 specification. Details ▾Hide ▴
VCEP rule
Not applicable in PMS2 VCEP
Evidence considered
- Criterion marked not applicable in PMS2 specification.
Sources
BP3 VCEPBP3 is not used in the PMS2 specification. Details ▾Hide ▴
VCEP rule
Not applicable in PMS2 VCEP
Evidence considered
- Criterion marked not applicable in PMS2 specification.
Sources
BP6 VCEPBP6 is not used in the PMS2 specification. Details ▾Hide ▴
VCEP rule
Not applicable in PMS2 VCEP
Evidence considered
- Criterion marked not applicable in PMS2 specification.
Sources
Identifiers
- Gene
- PMS2
- Transcript
- NM_000535.7
- Coding (HGVS c.)
- NM_000535.7:c.1128A>C
- Protein (HGVS p.)
- NP_000526.2:p.(Pro376=)
- GRCh38
- chr7:5989816 T>G
- GRCh37
- chr7:6029447 T>G
- ClinVar
- 135932
- COSMIC
- COSV56224632
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
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
121 / 1,612,348 alleles
AF 7.5e-05 · 0 homozygotes · FAF 8.43e-05
gnomAD v2.1
9 / 251,274 alleles
AF 3.58e-05 · 0 homozygotes · FAF 4.11e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 7.5e-05 · 121 / 1,612,348 alleles · 0 hom · FAF 8.4e-05
| European (non-Finnish)117 / 1,178,694 | 9.9e-05 |
| Remaining individuals4 / 62,394 | 6.4e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 3.6e-05 · 9 / 251,274 alleles · 0 hom · FAF 4.1e-05
| European (non-Finnish)9 / 113,718 | 7.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 7.50458e-05; MAF= 0.00750%, 121/1612348 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.92624e-05; MAF= 0.00993%, 117/1178694 alleles, homozygotes = 0); grpmax FAF= 8.433e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.58175e-05; MAF= 0.00358%, 9/251274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.91431e-05; MAF= 0.00791%, 9/113718 alleles, homozygotes = 0); grpmax FAF= 4.115e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingFor this synonymous variant, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is at or below the BP4 threshold of 0.1; this supports BP4. Details ▾Hide ▴
Rule
Synonymous or intronic variant with SpliceAI delta score <=0.1
Evidence considered
- SpliceAI max delta score 0.00.
Sources
BP7 SupportingThis is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the benign splicing threshold of 0.1; this supports BP7. Details ▾Hide ▴
Rule
Synonymous or qualifying intronic variant; may satisfy BP7 with no predicted splice impact
Evidence considered
- Synonymous change p.(Pro376=).
- SpliceAI max delta score 0.00.
Sources
PP3 This synonymous variant does not meet the PMS2 missense HCI-prior rule, no HCI prior entry was available for c.1128A>C, and SpliceAI predicts no splice defect with a maximum delta score of 0.00, which is below the PP3 splice threshold of 0.2; PP3 is not met. Details ▾Hide ▴
Rule
Missense HCI prior >0.68 or non-canonical splice variant with SpliceAI >=0.2
Evidence considered
- No HCI prior entry for c.1128A>C.
- SpliceAI max delta score 0.00.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
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PMID 25070057 ↗Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.Giardiello FM et al. · 2014No paper-specific finding is recorded.
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PMID 25645574 ↗ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.No paper-specific finding is recorded.
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PMID 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.No paper-specific finding is recorded.
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
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PMID 31672839 ↗Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.No paper-specific finding is recorded.
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PMID 11598466 ↗Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation.Church J et al. · 2001No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
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PMID 20301390 ↗Lynch Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
121 / 1,612,348 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
5 Likely benign · 2 Likely Benign · 1 Benign · 1 likely 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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1578297058
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/135932/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-6029447-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-5989816-T-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-5989816-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000535.7%3Ac.1128…
- OncoKB ↗www.oncokb.org/gene/PMS2/P376=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=125056088
- Cancer hotspots ↗www.cancerhotspots.org/
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= 7.50458e-05; MAF= 0.00750%, 121/1612348 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.92624e-05; MAF= 0.00993%, 117/1178694 alleles, homozygotes = 0); grpmax FAF= 8.433e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.58175e-05; MAF= 0.00358%, 9/251274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.91431e-05; MAF= 0.00791%, 9/113718 alleles, homozygotes = 0); grpmax FAF= 4.115e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Likely Benign (2 clinical laboratories) and as Benign (1 clinical laboratory) and as likely benign (1 clinical laboratory). (ClinVarID = 135932)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56224632, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.