About PMS2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PMS2 c.321G>A, p.(Arg107=)
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: 1
Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
Population frequency supports PM2 at supporting strength. In gnomAD v4.1, the allele frequency is 0.0000068831 (11/1598118 alleles) and the grpmax filtering allele frequency is 0.00000429, both below the PMS2 PM2 threshold of 0.00002.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
For this synonymous variant, SpliceAI predicts no splicing impact with a max delta score of 0.00, which is below the PMS2 BP4 threshold of 0.10 and supports BP4.
BP7Supporting
BP7 · supporting
This variant is a synonymous exonic substitution and is outside the PMS2 BP7 splice-region window; SpliceAI also predicts no significant splice impact, which is consistent with BP7 being met.
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, PM2 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
11 / 1,598,118 alleles
gnomAD v4.1: 11 / 1,598,118 alleles. Recorded AF 6.8831e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.11366e-05; MAF= 0.00211%, 5/236556 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.66381e-05; MAF= 0.00366%, 4/109176 alleles, homozygotes = 0); grpmax FAF= 1.156e-05.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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: 3 met · 4 not met · 9 not assessed · 12 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.321G>A (p.Arg107=) variant has been reported in ClinVar predominantly as likely benign or benign, with a minority submission as uncertain significance.
This variant is present at very low frequency in population databases, including gnomAD v4.1 at 11/1598118 alleles (AF 0.0000068831; grpmax FAF 0.00000429) and gnomAD v2.1 at 5/236556 alleles (AF 0.0000211366), which is below the PMS2 PM2_Supporting threshold of 0.00002 in gnomAD v4 and far below the BS1 and BA1 thresholds.
In silico evidence supports a benign interpretation because this synonymous variant has no predicted splice effect by SpliceAI, with a maximum delta score of 0.00, supporting BP4 and consistent with BP7.
No criteria match.
Met · 3
PM2 SupportingPopulation frequency supports PM2 at supporting strength. In gnomAD v4.1, the allele frequency is 0.0000068831 (11/1598118 alleles) and the grpmax filtering allele frequency is 0.00000429, both below the PMS2 PM2 threshold of 0.00002. Details ▾Hide ▴
Rule
PMS2 CSPEC PM2 Supporting
Evidence considered
- gnomAD v4 total AF = 6.8831e-06 (11/1598118)
- gnomAD v4 grpmax FAF = 4.29e-06
- PM2 threshold = <2e-05
Sources
BP4 SupportingFor this synonymous variant, SpliceAI predicts no splicing impact with a max delta score of 0.00, which is below the PMS2 BP4 threshold of 0.10 and supports BP4. Details ▾Hide ▴
Rule
PMS2 CSPEC BP4 Supporting
Evidence considered
- SpliceAI max delta score = 0.00
- BP4 threshold for synonymous/intronic variants: <=0.10
Sources
BP7 SupportingThis variant is a synonymous exonic substitution and is outside the PMS2 BP7 splice-region window; SpliceAI also predicts no significant splice impact, which is consistent with BP7 being met. Details ▾Hide ▴
Rule
PMS2 CSPEC BP7 Supporting
Evidence considered
- p.(Arg107=) synonymous variant
- SpliceAI max delta score = 0.00
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 PVS1 is not met because this variant is a synonymous substitution rather than a null variant, and SpliceAI predicts no significant splice impact. The generic PVS1 assessment also found that this variant does not fall into a default PVS1 null-variant category. Details ▾Hide ▴
Rule
PMS2 CSPEC PVS1
Evidence considered
- p.(Arg107=) synonymous variant
- SpliceAI max delta score = 0.00
- Generic PVS1 scaffold: not a null-variant bucket
Sources
PP3 Computational evidence does not support PP3. This variant is not missense, and SpliceAI predicts no splice defect with a max delta score of 0.00, which is below the PMS2 PP3 splice threshold of 0.20. Details ▾Hide ▴
Rule
PMS2 CSPEC PP3
Evidence considered
- Synonymous variant
- SpliceAI max delta score = 0.00
- PP3 splice threshold = >=0.20
Sources
BA1 Population frequency does not meet BA1. The gnomAD v4 grpmax filtering allele frequency is 0.00000429, which is below the BA1 threshold of 0.0028 (0.28%). Details ▾Hide ▴
Rule
PMS2 CSPEC BA1
Evidence considered
- gnomAD v4 grpmax FAF = 4.29e-06
- BA1 threshold = 0.0028
Sources
BS1 Population frequency does not meet BS1. The gnomAD v4 grpmax filtering allele frequency is 0.00000429, which is below the BS1 threshold of 0.00028 (0.028%). Details ▾Hide ▴
Rule
PMS2 CSPEC BS1
Evidence considered
- gnomAD v4 grpmax FAF = 4.29e-06
- BS1 threshold = 0.00028
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo occurrence with the tumor features required by the PMS2 specification was identified, so PS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
PMS2 CSPEC PS2
Evidence considered
- No de novo data identified
Still missing
- Confirmed maternity and paternity
- Associated MSI/IHC tumor data consistent with PMS2
Sources
PS3 No calibrated functional assay result or RNA study showing a damaging effect for this specific variant was identified, so PS3 cannot be applied. Details ▾Hide ▴
Rule
PMS2 CSPEC PS3
Evidence considered
- No variant-specific damaging functional evidence identified
Still missing
- Variant-specific calibrated functional assay data
- Variant-specific RNA assay data
Sources
cspec ↗vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___s_v_i___d_o_c_u_m_e_n_t_a_t_i_o_n___m_m_rvcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___f_l_o_w_c_h_a_r_t
PM3 No evidence was identified that this variant occurs in trans with another pathogenic PMS2 variant in a context informative for constitutional mismatch repair deficiency scoring, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
PMS2 CSPEC PM3
Evidence considered
- No qualifying PM3 observations identified
Still missing
- Confirmed trans observations
- CMMRD phenotype details
- PM3 point-based evidence
Sources
cspec ↗vcep_t_a_b_l_e___f_o_r___c_m_m_r_d___d_i_a_g_n_o_s_i_s
PP1 No segregation data were identified, so the Bayes likelihood ratio required for PP1 could not be calculated. Details ▾Hide ▴
Rule
PMS2 CSPEC PP1
Evidence considered
- No segregation evidence identified
Still missing
- Pedigree-level segregation data
- Bayes likelihood ratio
Sources
PP4 No colorectal or endometrial tumor MSI results, tumor genome findings, or immunohistochemistry results consistent with PMS2 loss were identified, so PP4 cannot be applied. Details ▾Hide ▴
Rule
PMS2 CSPEC PP4
Evidence considered
- No qualifying tumor phenotype data identified
Still missing
- MSI testing
- MMR immunohistochemistry
- Tumor count and family-level tumor information
Sources
BS2 No evidence was identified that this variant co-occurs in trans with a known pathogenic PMS2 variant in an individual meeting the specification requirements for age and absence of CMMRD features, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
PMS2 CSPEC BS2
Evidence considered
- No qualifying in trans co-occurrence data identified
Still missing
- Confirmed trans phase
- Clinical details excluding CMMRD
- Age and cancer phenotype details
Sources
cspec ↗vcep_t_a_b_l_e___f_o_r___c_m_m_r_d___d_i_a_g_n_o_s_i_s
BS3 No variant-specific functional or RNA assay result demonstrating normal function or no mRNA aberration was identified, so BS3 cannot be applied. Details ▾Hide ▴
Rule
PMS2 CSPEC BS3
Evidence considered
- No variant-specific benign functional evidence identified
Still missing
- Variant-specific benign functional assay data
- Variant-specific RNA assay data with NMD inhibition when applicable
Sources
cspec ↗vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___s_v_i___d_o_c_u_m_e_n_t_a_t_i_o_n___m_m_rvcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___f_l_o_w_c_h_a_r_t
BS4 No non-segregation data were identified, so the Bayes likelihood ratio required for BS4 could not be calculated. Details ▾Hide ▴
Rule
PMS2 CSPEC BS4
Evidence considered
- No non-segregation evidence identified
Still missing
- Pedigree-level non-segregation data
- Bayes likelihood ratio
Sources
BP5 No tumor data were identified showing microsatellite-stable disease, retained mismatch repair protein expression, or protein loss inconsistent with PMS2, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
PMS2 CSPEC BP5
Evidence considered
- No qualifying inconsistent tumor evidence identified
Still missing
- Tumor MSI results
- Tumor immunohistochemistry
- BRAF or MLH1 methylation data where relevant
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis criterion is not applicable because this variant is a synonymous substitution without predicted splice impact, whereas the PMS2 specification uses PS1 for same-amino-acid missense substitutions or variants affecting the same non-canonical splice nucleotide as an established splice variant. Details ▾Hide ▴
Rule
PMS2 CSPEC PS1
Evidence considered
- NM_000535.7:c.321G>A is synonymous
- p.(Arg107=)
- SpliceAI max delta score = 0.00
Sources
PS4 N/AThis criterion is not used for PMS2 in the applicable specification. Details ▾Hide ▴
PM1 N/AThis criterion is not used for PMS2 in the applicable specification. Details ▾Hide ▴
PM4 N/AThis criterion is not used for PMS2 in the applicable specification. Details ▾Hide ▴
PM5 N/AThis criterion is not applicable because PM5 is defined for missense changes at an amino acid residue with another pathogenic or likely pathogenic missense change, and this variant is synonymous. Details ▾Hide ▴
Rule
PMS2 CSPEC PM5
Evidence considered
- p.(Arg107=) synonymous variant
- No applicable missense-based PM5 scenario
Sources
cspec ↗vcep_v_c_e_p___p_i_l_o_t___v_a_r_i_a_n_t_s_______m_m_r
PM6 N/AThis criterion is not used for PMS2 in the applicable specification. Details ▾Hide ▴
PP2 N/AThis criterion is not used for PMS2 in the applicable specification. Details ▾Hide ▴
PP5 N/AThis criterion is not used for PMS2 in the applicable specification. Details ▾Hide ▴
BP1 N/AThis criterion is not used for PMS2 in the applicable specification. Details ▾Hide ▴
BP2 N/AThis criterion is not used for PMS2 in the applicable specification. Details ▾Hide ▴
BP3 N/AThis criterion is not used for PMS2 in the applicable specification. Details ▾Hide ▴
BP6 N/AThis criterion is not used for PMS2 in the applicable specification. Details ▾Hide ▴
Identifiers
- Gene
- PMS2
- Transcript
- NM_000535.7
- Coding (HGVS c.)
- NM_000535.7:c.321G>A
- Protein (HGVS p.)
- NP_000526.2:p.(Arg107=)
- GRCh38
- chr7:6003722 C>T
- GRCh37
- chr7:6043353 C>T
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
11 / 1,598,118 alleles
AF 6.88e-06 · 0 homozygotes · FAF 4.29e-06
gnomAD v2.1
5 / 236,556 alleles
AF 2.11e-05 · 0 homozygotes · FAF 1.16e-05
By genetic ancestry
gnomAD v4.1
AF 6.9e-06 · 11 / 1,598,118 alleles · 0 hom · FAF 4.3e-06
| Admixed American1 / 59,956 | 1.7e-05 |
| European (non-Finnish)10 / 1,178,204 | 8.5e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 2.1e-05 · 5 / 236,556 alleles · 0 hom · FAF 1.2e-05
| European (non-Finnish)4 / 109,176 | 3.7e-05 |
| Admixed American1 / 34,424 | 2.9e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.8831e-06; MAF= 0.00069%, 11/1598118 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66789e-05; MAF= 0.00167%, 1/59956 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.11366e-05; MAF= 0.00211%, 5/236556 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.66381e-05; MAF= 0.00366%, 4/109176 alleles, homozygotes = 0); grpmax FAF= 1.156e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingFor this synonymous variant, SpliceAI predicts no splicing impact with a max delta score of 0.00, which is below the PMS2 BP4 threshold of 0.10 and supports BP4. Details ▾Hide ▴
Rule
PMS2 CSPEC BP4 Supporting
Evidence considered
- SpliceAI max delta score = 0.00
- BP4 threshold for synonymous/intronic variants: <=0.10
Sources
BP7 SupportingThis variant is a synonymous exonic substitution and is outside the PMS2 BP7 splice-region window; SpliceAI also predicts no significant splice impact, which is consistent with BP7 being met. Details ▾Hide ▴
Rule
PMS2 CSPEC BP7 Supporting
Evidence considered
- p.(Arg107=) synonymous variant
- SpliceAI max delta score = 0.00
Sources
PP3 Computational evidence does not support PP3. This variant is not missense, and SpliceAI predicts no splice defect with a max delta score of 0.00, which is below the PMS2 PP3 splice threshold of 0.20. Details ▾Hide ▴
Rule
PMS2 CSPEC PP3
Evidence considered
- Synonymous variant
- SpliceAI max delta score = 0.00
- PP3 splice threshold = >=0.20
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
11 / 1,598,118 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/231811/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-6043353-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-6003722-C-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000535.7%3Ac.321G…
- OncoKB ↗www.oncokb.org/gene/PMS2/R107=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PMS2+c.321G%3EA
- 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= 6.8831e-06; MAF= 0.00069%, 11/1598118 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66789e-05; MAF= 0.00167%, 1/59956 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.11366e-05; MAF= 0.00211%, 5/236556 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.66381e-05; MAF= 0.00366%, 4/109176 alleles, homozygotes = 0); grpmax FAF= 1.156e-05.
ClinVar
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
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.