About PMS2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PMS2 c.830C>A, p.(Thr277Lys)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A 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
BA1Stand alone
BA1 · stand alone
The VCEP BA1 rule is met: gnomAD v4.1 grpmax filtering allele frequency is 0.00408 (0.408%), exceeding the BA1 threshold of ≥0.0028 (0.28%). One homozygote is present in gnomAD v4.1. The variant is enriched in the African/African American population (AF=0.448%) consistent with a population-specific polymorphism rather than a founder pathogenic variant; PMS2 pathogenic variants causing Lynch syndrome are incompatible with a homozygote in a general population database, as homozygosity would cause constitutional mismatch repair deficiency (CMMRD).
BP4Supporting
BP4 · supporting
The VCEP BP4_Supporting rule is met: the HCI prior probability for c.830C>A (p.Thr277Lys) is 0.0013, which is below the BP4_Supporting threshold of <0.11. Multiple additional in silico predictors support a benign interpretation: REVEL score 0.251, BayesDel score -0.187, and SpliceAI max delta 0.03 (no predicted splicing impact).
Recorded classification: 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 Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BP4 supporting; maps to 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
385 / 1,613,328 alleles
gnomAD v4.1: 385 / 1,613,328 alleles. Recorded AF 0.000238637. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000417215; MAF= 0.04172%, 118/282828 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00456694; MAF= 0.45669%, 114/24962 alleles, homozygotes = 0); grpmax FAF= 0.00406668.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001086484137331595, 2/18408 alleles, homozygotes = 0).
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
19 reported laboratory submissions
9 Benign · 7 Likely benign · 2 Uncertain significance · 1 Likely Benign.
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
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 · 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
BA1 (Stand-Alone) is met: the gnomAD v4.1 grpmax filtering allele frequency is 0.408%, exceeding the VCEP BA1 threshold of 0.28%, with one homozygote present in the database, excluding this variant as a cause of Lynch syndrome due to PMS2.
BP4 (Supporting) is met: the HCI prior probability for pathogenicity is 0.0013, below the BP4_Supporting threshold of <0.11, with multiple in silico predictors (REVEL 0.251, BayesDel -0.187, SpliceAI max delta 0.03) consistent with a benign computational profile.
This variant has been reported in ClinVar as Benign by 9 clinical laboratories, Likely Benign by 8 laboratories, and Uncertain Significance by 2 laboratories (ClinVar Variation ID: 135946).
PP3 is not met: the HCI prior of 0.0013 is far below the PP3_Supporting threshold of >0.68.
PM2_Supporting is not met: the gnomAD v4.1 allele frequency of 0.0239% exceeds the PM2 threshold of <0.002%.
No criteria match.
Met · 2
BA1 Stand aloneThe VCEP BA1 rule is met: gnomAD v4.1 grpmax filtering allele frequency is 0.00408 (0.408%), exceeding the BA1 threshold of ≥0.0028 (0.28%). One homozygote is present in gnomAD v4.1. The variant is enriched in the African/African American population (AF=0.448%) consistent with a population-specific polymorphism rather than a founder pathogenic variant; PMS2 pathogenic variants causing Lynch syndrome are incompatible with a homozygote in a general population database, as homozygosity would cause constitutional mismatch repair deficiency (CMMRD). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: grpmax FAF=0.00408 (0.408%)
- exceeding BA1 threshold of 0.28%. One homozygote present. African/African American subpopulation AF=0.448%. Absent from gnomAD-Canada v1.0.
Sources
BP4 SupportingThe VCEP BP4_Supporting rule is met: the HCI prior probability for c.830C>A (p.Thr277Lys) is 0.0013, which is below the BP4_Supporting threshold of <0.11. Multiple additional in silico predictors support a benign interpretation: REVEL score 0.251, BayesDel score -0.187, and SpliceAI max delta 0.03 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- HCI prior 0.0013 (<0.11 BP4 threshold). REVEL 0.251. BayesDel -0.187. SpliceAI max delta 0.03. All computational predictors consistent with benign effect.
Sources
Not met · 4 · evaluated, threshold not reached
PM2 The VCEP PM2_Supporting rule requires gnomAD v4 allele frequency <0.00002 (<1 in 50,000 alleles). This variant has an allele frequency of 0.000239 (385/1,613,328 alleles) in gnomAD v4.1, exceeding the PM2 threshold by more than tenfold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 385/1
- 613
- 328 alleles (AF=0.0239%)
- well above the PM2_Supporting threshold of <0.002%.
Sources
PM5 The VCEP PM5 rule requires PP3 to be supporting for the missense change, and a different missense at the same residue (Thr277) classified as Pathogenic or Likely Pathogenic by this VCEP. PP3 is not met (HCI prior 0.0013). Additionally, PM5 candidate search identified zero comparator candidates at this residue. Details ▾Hide ▴
Evidence considered
- PP3 not met
- PM5 requires PP3_Supporting. Zero comparator candidates found at codon 277.
Sources
cspec ↗pm5_candidates
PP3 The VCEP PP3 rule uses the HCI prior probability for pathogenicity. PP3_Supporting requires HCI prior >0.68 and ≤0.81; PP3_Moderate requires >0.81. The HCI prior for c.830C>A (p.Thr277Lys) is 0.0013, well below both thresholds. SpliceAI predicts no splicing impact (max delta score 0.03), and REVEL (0.251) and BayesDel (-0.187) are consistent with a benign computational profile. Details ▾Hide ▴
Evidence considered
- HCI prior probability 0.0013 (thresholds: >0.68 Supporting
- >0.81 Moderate). SpliceAI max delta 0.03. REVEL 0.251. BayesDel -0.187.
Sources
BS1 The VCEP BS1 threshold is ≥0.00028 (0.028%) and <0.0028 (0.28%). The gnomAD v4.1 grpmax FAF of 0.00408 (0.408%) exceeds the upper bound of the BS1 range, placing this variant in BA1 territory instead. Details ▾Hide ▴
Not assessed · 9 · no assessment recorded
PS1 PS1 requires a different nucleotide change encoding the same amino acid (Thr277Lys) previously classified as Pathogenic by this VCEP. No such comparator variant was identified in the VCEP pilot variants spreadsheet or in ClinVar with a VCEP-level Pathogenic classification at this codon. Details ▾Hide ▴
Still missing
- No established Pathogenic or Likely Pathogenic missense comparator at codon 277 with a different nucleotide change was found in VCEP resources or ClinVar.
PS2 No de novo occurrence of NM_000535.7:c.830C>A has been reported in any published study or database. Exploratory literature and database search yielded no de novo observations. Details ▾Hide ▴
Still missing
- No de novo reports identified in published literature or databases for this variant.
PS3 No variant-specific functional assay data for NM_000535.7:c.830C>A (p.Thr277Lys) were confirmed from the available evidence. The exploratory search referenced Drost et al. (PMID:30504929) as a potential source, but variant-specific functional results were not retrieved. The VCEP functional assay documentation spreadsheet lists assay types but does not contain variant-level functional classifications. Details ▾Hide ▴
Still missing
- Variant-specific MMR functional assay results from Drost et al. (PMID:30504929) or other calibrated assays not confirmed for this variant.
PP1 No co-segregation data are available for this variant in families with Lynch syndrome or CMMRD. Exploratory search did not identify any published segregation analysis. Details ▾Hide ▴
Still missing
- No family-based co-segregation data identified in the literature or LSDBs.
PP4 No tumor MSI/IHC data are available for individuals carrying this variant. PP4 requires MSI-H tumors or loss of MMR protein expression consistent with the variant location in PMS2. Details ▾Hide ▴
Still missing
- No tumor MSI status or MMR IHC data available for carriers of this variant.
BS2 No data are available on co-occurrence of this variant in trans with a known pathogenic PMS2 variant in a patient with colorectal cancer after age 45 without CMMRD features. Details ▾Hide ▴
Still missing
- No trans co-occurrence data with a known pathogenic PMS2 variant identified.
BS3 No variant-specific functional assay data confirming normal MMR function for NM_000535.7:c.830C>A were identified. The VCEP functional assay documentation spreadsheet does not contain variant-level results. The exploratory search identified Drost et al. as a potential source, but variant-specific functional classification was not confirmed. Details ▾Hide ▴
Still missing
- Variant-specific MMR functional results from calibrated assays not confirmed for this variant.
BS4 No family-based lack of co-segregation data are available for this variant. Exploratory search did not identify any published segregation or non-segregation analysis. Details ▾Hide ▴
Still missing
- No co-segregation or lack-of-segregation data identified for this variant.
BP5 No tumor data (MSS CRC/endometrial tumors, retained MMR protein expression, BRAF V600E, or MLH1 methylation) are available for carriers of this variant. BP5 requires tumor-based evidence of intact mismatch repair inconsistent with a PMS2 pathogenic variant. Details ▾Hide ▴
Still missing
- No tumor phenotype data available for carriers of this variant.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000535.7:c.830C>A is a missense variant (p.Thr277Lys). PVS1 under the InSiGHT PMS2 VCEP v2.0.0 applies only to null variants (nonsense, frameshift, canonical ±1/2 splice sites, initiation codon, large genomic alterations) and is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- Missense variant in exon 8
- not a null variant under any PVS1 strength rule in the PMS2 VCEP decision tree.
Sources
cspec ↗pvs1_variant_assessment
PS4 VCEPPS4 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework. Details ▾Hide ▴
PM1 VCEPPM1 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework. Details ▾Hide ▴
PM6 VCEPPM6 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework. Details ▾Hide ▴
PP2 VCEPPP2 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework. Details ▾Hide ▴
PP5 VCEPPP5 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework. This criterion is not used for PMS2 variant classification under this VCEP. Details ▾Hide ▴
BP1 VCEPBP1 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework. Details ▾Hide ▴
BP2 VCEPBP2 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework. Details ▾Hide ▴
BP3 VCEPBP3 is trivially not applicable (in-frame indels in repetitive regions); this is a single nucleotide substitution. Also explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not an in-frame indel in a repetitive region.
Sources
BP6 VCEPBP6 is explicitly marked as Not Applicable in the InSiGHT PMS2 VCEP v2.0.0 framework. Details ▾Hide ▴
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. NM_000535.7:c.830C>A is a missense variant (p.Thr277Lys) and does not meet BP7 criteria. Details ▾Hide ▴
PS5 N/APS5 is not defined in the InSiGHT PMS2 VCEP v2.0.0 framework. No VCEP rules exist for this criterion in this gene. Details ▾Hide ▴
Identifiers
- Gene
- PMS2
- Transcript
- NM_000535.7
- Coding (HGVS c.)
- NM_000535.7:c.830C>A
- Protein (HGVS p.)
- NP_000526.2:p.(Thr277Lys)
- GRCh38
- chr7:5995607 G>T
- GRCh37
- chr7:6035238 G>T
- ClinVar
- 135946
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
385 / 1,613,328 alleles
AF 0.000239 · 1 homozygotes · FAF 0.00408
gnomAD v2.1
118 / 282,828 alleles
AF 0.000417 · 0 homozygotes · FAF 0.00407
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00024 · 385 / 1,613,328 alleles · 1 hom · FAF 0.0041
| African/African American336 / 75,016 | 0.00451 hom |
| Middle Eastern3 / 6,060 | 0.0005 |
| Remaining individuals29 / 62,484 | 0.00046 |
| Admixed American9 / 59,976 | 0.00015 |
| South Asian4 / 91,060 | 4.4e-05 |
| European (non-Finnish)4 / 1,179,316 | 3.4e-06 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00042 · 118 / 282,828 alleles · 0 hom · FAF 0.0041
| African/African American114 / 24,962 | 0.0046 |
| South Asian1 / 30,616 | 3.3e-05 |
| Admixed American1 / 35,440 | 2.8e-05 |
| European (non-Finnish)2 / 129,140 | 1.5e-05 |
0 alternate alleles recorded in 4 other groups: Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000238637; MAF= 0.02386%, 385/1613328 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00447904; MAF= 0.44790%, 336/75016 alleles, homozygotes = 1); grpmax FAF= 0.00408391.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000417215; MAF= 0.04172%, 118/282828 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00456694; MAF= 0.45669%, 114/24962 alleles, homozygotes = 0); grpmax FAF= 0.00406668.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001086484137331595, 2/18408 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.251
- BayesDel
- -0.187
How the predictions were used
BP4 SupportingThe VCEP BP4_Supporting rule is met: the HCI prior probability for c.830C>A (p.Thr277Lys) is 0.0013, which is below the BP4_Supporting threshold of <0.11. Multiple additional in silico predictors support a benign interpretation: REVEL score 0.251, BayesDel score -0.187, and SpliceAI max delta 0.03 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- HCI prior 0.0013 (<0.11 BP4 threshold). REVEL 0.251. BayesDel -0.187. SpliceAI max delta 0.03. All computational predictors consistent with benign effect.
Sources
PP3 The VCEP PP3 rule uses the HCI prior probability for pathogenicity. PP3_Supporting requires HCI prior >0.68 and ≤0.81; PP3_Moderate requires >0.81. The HCI prior for c.830C>A (p.Thr277Lys) is 0.0013, well below both thresholds. SpliceAI predicts no splicing impact (max delta score 0.03), and REVEL (0.251) and BayesDel (-0.187) are consistent with a benign computational profile. Details ▾Hide ▴
Evidence considered
- HCI prior probability 0.0013 (thresholds: >0.68 Supporting
- >0.81 Moderate). SpliceAI max delta 0.03. REVEL 0.251. BayesDel -0.187.
Sources
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. NM_000535.7:c.830C>A is a missense variant (p.Thr277Lys) and does not meet BP7 criteria. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.251. BayesDel score = -0.187245. HCI prior probability for pathogenicity = 0.0013. MAPP score = 3.08. Custom PP2 score = 0.007.
9 paper records listed. 1 cited in the classification.
Cited in the classification
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PMID 22949387 ↗Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.Thompson BA et al. · 2013 JanThompson et al. (2013) calibrated multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. The variant NM_000535.7:c.830C>A (p.Thr277Lys) is included in the supplementary HCI priors table with an MAPP/PP2 prior probability of 0.0013, MAPP score 3.08, and custom PP2 score 0.007.→ BP4 Names this variant
Source detail
c.830C>A, p.T277K, custom PP2 score 0.007, MAPP score 3.08, MAPP/PP2 Prior 0.0013
Location Supplementary Table (HCI priors database); variant entry PMS2_01804
Other recorded publications
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PMID 17417778 ↗Genetic investigation of DNA-repair pathway genes PMS2, MLH1, MSH2, MSH6, MUTYH, OGG1 and MTH1 in sporadic colon cancer.Schafmayer C et al. · 2007Schafmayer et al. (2007) investigated DNA repair pathway genes including PMS2 in sporadic colon cancer. The abstract discusses gene-level associations. NM_000535.7:c.830C>A was not identified in the abstract or available evidence.Does not name this variant
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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. · 2014Giardiello et al. (2014) Multi-Society Task Force guidelines on genetic evaluation and management of Lynch syndrome. This is a clinical practice guideline. NM_000535.7:c.830C>A was not identified in the abstract.Does not name this variant
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PMID 25645574 ↗ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.Syngal et al. (2015) ACG clinical guideline on genetic testing and management of hereditary gastrointestinal cancer syndromes. NM_000535.7:c.830C>A was not identified in this paper.Does not name this variant
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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.Richards et al. (2015) ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a general framework paper. NM_000535.7:c.830C>A was not identified in the text.Does not name this variant
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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. · 2001Church et al. (2001) practice parameters for identification and testing of patients at risk for dominantly inherited colorectal cancer. NM_000535.7:c.830C>A was not identified in this paper.Does not name this variant
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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.Nykamp et al. (2017) Sherloc refinement of ACMG-AMP variant classification criteria. This is a general framework paper. NM_000535.7:c.830C>A was not identified in the abstract.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
385 / 1,613,328 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
9 Benign · 7 Likely benign · 2 Uncertain significance · 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/135946/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-6035238-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-5995607-G-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-5995607-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000535.7%3Ac.830C…
- OncoKB ↗www.oncokb.org/gene/PMS2/T277K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PMS2+c.830C%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= 0.000238637; MAF= 0.02386%, 385/1613328 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00447904; MAF= 0.44790%, 336/75016 alleles, homozygotes = 1); grpmax FAF= 0.00408391.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000417215; MAF= 0.04172%, 118/282828 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00456694; MAF= 0.45669%, 114/24962 alleles, homozygotes = 0); grpmax FAF= 0.00406668.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001086484137331595, 2/18408 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Benign (9 clinical laboratories) and as Likely benign (7 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely Benign (1 clinical laboratory). (ClinVarID = 135946)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.251. BayesDel score = -0.187245. HCI prior probability for pathogenicity = 0.0013. MAPP score = 3.08. Custom PP2 score = 0.007.
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.