About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.866G>A, p.(Gly289Asp)
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 MSH6 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
BS1Strong
BS1 · strong
Population frequency meets the MSH6 BS1 threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 0.00024593, which is above the BS1 threshold of 0.00022 and below the BA1 threshold of 0.0022.
BP4Supporting
BP4 · supporting
Computational evidence supports a benign interpretation. For this MSH6 missense variant, the HCI prior probability is 0.0021, which is below the BP4 threshold of 0.11. Additional predictors do not suggest a damaging effect, with REVEL 0.272, BayesDel -0.256015, and SpliceAI max delta 0.01 indicating no significant splice impact.
Recorded classification: Likely benign
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0.0 v2.0.0 criteria-combination framework: matched Rule18 (1 Benign.Strong + 1 Benign.Supporting) with applied criteria: BS1 strong, 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
350 / 1,614,052 alleles
gnomAD v4.1: 350 / 1,614,052 alleles. Recorded AF 0.000216846. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 9.20165e-05; MAF= 0.00920%, 26/282558 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000193865; MAF= 0.01939%, 25/128956 alleles, homozygotes = 0); grpmax FAF= 0.00012357.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
3 Uncertain significance · 1 Benign · 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. MSH6, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial 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 MSH6 VCEP v2.0.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 11 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The MSH6 c.866G>A (p.Gly289Asp; p.G289D) variant has not been observed in COSMIC and has been reported in ClinVar with conflicting germline classifications, including uncertain significance, likely benign, and benign submissions.
This variant is present in gnomAD v4.1 at an allele frequency of 0.000216846 (350/1614052 alleles) with grpmax filtering allele frequency 0.00024593, which exceeds the MSH6 BS1 threshold of 0.00022 but remains below the BA1 threshold of 0.0022.
Computational data support a benign interpretation: the MSH6 HCI prior probability is 0.0021, below the BP4 threshold of 0.11, SpliceAI predicts no significant splice impact with a max delta score of 0.01, and additional predictors are not strongly damaging (REVEL 0.272; BayesDel -0.256015).
No criteria match.
Met · 2
BS1 StrongPopulation frequency meets the MSH6 BS1 threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 0.00024593, which is above the BS1 threshold of 0.00022 and below the BA1 threshold of 0.0022. Details ▾Hide ▴
Rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 and < 0.0022 (0.022-0.22%) and variant is excluded as founder pathogenic variant.
Evidence considered
- gnomAD v4.1 grpmax FAF 0.00024593
- MSH6 BS1 threshold 0.00022
- MSH6 BA1 threshold 0.0022
Sources
BP4 SupportingComputational evidence supports a benign interpretation. For this MSH6 missense variant, the HCI prior probability is 0.0021, which is below the BP4 threshold of 0.11. Additional predictors do not suggest a damaging effect, with REVEL 0.272, BayesDel -0.256015, and SpliceAI max delta 0.01 indicating no significant splice impact. Details ▾Hide ▴
Rule
Missense variant with HCI-prior probability of pathogenicity <0.11.
Evidence considered
- HCI prior 0.0021
- REVEL 0.272
- BayesDel -0.256015
- SpliceAI max delta 0.01
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, p.(Gly289Asp), and does not fall into the MSH6 PVS1 null-variant categories. The reviewed PVS1 assessments indicate that it is not a nonsense, frameshift, canonical ±1/2 splice, initiation codon, or proven splice-aberrant loss-of-function variant. Details ▾Hide ▴
Rule
MSH6 PVS1 applies to specified loss-of-function and qualifying splice-aberrant variants, with strength based on variant type and predicted consequence.
Evidence considered
- MSH6-specific PVS1 framework reviewed
- Generic PVS1 scaffold indicates variant bucket other
Sources
PM2 Population frequency is too high for PM2. In gnomAD v4.1, the allele frequency is 0.000216846 (350/1614052 alleles), which is above the MSH6 PM2 threshold of <0.00002. Details ▾Hide ▴
Rule
Absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 AF 0.000216846 (350/1614052)
- MSH6 PM2 threshold <0.00002
Sources
PP3 Computational evidence does not support pathogenicity under the MSH6 missense PP3 rule. The HCI prior probability is 0.0021, which is below the PP3 thresholds of >0.68 for supporting and >0.81 for moderate evidence. SpliceAI also does not predict a splice defect, with a max delta score of 0.01, below the non-canonical splice threshold of 0.2. Details ▾Hide ▴
Rule
Missense variant with HCI prior probability for pathogenicity >0.68 (supporting) or >0.81 (moderate), or predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score ≥0.2.
Evidence considered
- HCI prior 0.0021
- SpliceAI max delta 0.01
Sources
BA1 Population frequency does not meet the MSH6 BA1 threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 0.00024593, which is below the BA1 threshold of 0.0022 (0.22%). Details ▾Hide ▴
Rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%) and variant is excluded as founder pathogenic variant.
Evidence considered
- gnomAD v4.1 grpmax FAF 0.00024593
- MSH6 BA1 threshold 0.0022
Sources
Not assessed · 11 · no assessment recorded
PS1 No previously established pathogenic or likely pathogenic variant causing the same amino acid change by a different nucleotide change was identified in the reviewed materials. Details ▾Hide ▴
Rule
Same amino acid change as a previously established Pathogenic or Likely Pathogenic variant, subject to the MSH6 VCEP splice-related restrictions.
Evidence considered
- MSH6 PS1 rule reviewed
- ClinVar summary reviewed
Still missing
- Verified same-amino-acid comparator established by the governing framework
Sources
PS2 No confirmed de novo data were identified for this variant. Details ▾Hide ▴
Rule
De novo points-based scoring for supporting, moderate, strong, or very strong evidence.
Evidence considered
- MSH6 PS2 rule reviewed
Still missing
- De novo occurrence data with parental confirmation and phenotype details
Sources
PS3 No calibrated functional assay result or variant-specific mismatch repair defect meeting the MSH6 PS3 requirements was identified in the reviewed materials. Details ▾Hide ▴
Rule
Calibrated functional assays with functional odds for pathogenicity >2.08, or MMR function defect following the MMR functional assay flowchart, with strength based on odds or assay result.
Evidence considered
- MSH6 PS3 rule reviewed
- No variant-specific assay hit identified in reviewed VCEP materials
Still missing
- Variant-specific calibrated functional assay evidence
- Variant-specific protein/RNA assay evidence showing MMR dysfunction
Sources
PM3 No qualifying in trans observations in the recessive/CMMRD framework were identified for this variant. Details ▾Hide ▴
Rule
Points-based in trans evidence for pathogenicity with supporting, moderate, strong, or very strong strength.
Evidence considered
- MSH6 PM3 rule reviewed
Still missing
- Confirmed in trans observations with point scoring under the MSH6 PM3 framework
Sources
PM5 The MSH6 framework uses classic same-residue PM5 logic for missense variants, but no verified same-residue pathogenic or likely pathogenic comparator variant for codon 289 was identified in the reviewed materials. PM5 therefore cannot be applied at this time. Details ▾Hide ▴
Rule
Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic or Likely Pathogenic on the protein level and not due to aberrant splicing; PM5 use also requires PP3 support for the missense change.
Evidence considered
- PM5 candidate artifact reviewed
- No comparator candidates identified
Still missing
- Verified same-residue pathogenic or likely pathogenic missense comparator established on the protein level and not due to aberrant splicing
Sources
pm5_candidatescspec ↗
PP1 No segregation data were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
Rule
Co-segregation with disease in pedigree(s) with combined Bayes likelihood ratio thresholds for supporting, moderate, or strong evidence.
Evidence considered
- MSH6 PP1 rule reviewed
Still missing
- Pedigree-level segregation data with Bayes likelihood ratio
Sources
PP4 No tumor MSI or mismatch repair immunohistochemistry findings were identified to support the MSH6 PP4 phenotype-specific rule. Details ▾Hide ▴
Rule
1/2/≥3 independent CRC or endometrial MSI-H tumors and/or loss of MMR protein expression consistent with the variant location, with strength based on amount of evidence.
Evidence considered
- MSH6 PP4 rule reviewed
Still missing
- MSI testing results
- MMR protein expression results
- Family-level tumor count information
Sources
BS2 No confirmed observation of this variant in trans with a known pathogenic MSH6 variant in an individual meeting the MSH6 BS2 requirements was identified. Details ▾Hide ▴
Rule
Co-occurrence in trans with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 (or other LS cancer above the median age of onset for that cancer in LS), without evidence of CMMRD; confirmation of phase requires testing of parents or offspring.
Evidence considered
- MSH6 BS2 rule reviewed
Still missing
- Phase-confirmed in trans data
- Clinical information excluding CMMRD features
Sources
BS3 No calibrated functional assay result or variant-specific protein and RNA assay result meeting the MSH6 BS3 requirements was identified. Details ▾Hide ▴
Rule
Calibrated functional assays with functional odds for pathogenicity ≤ 0.05, or supporting evidence from proficient function in protein and mRNA-based assays per the MMR functional assay flowchart.
Evidence considered
- MSH6 BS3 rule reviewed
- No variant-specific assay hit identified in reviewed VCEP materials
Still missing
- Variant-specific calibrated functional assay evidence
- Variant-specific RNA assay evidence if available
Sources
BS4 No lack-of-segregation data were identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
Rule
Lack of co-segregation with disease in pedigree(s) with combined Bayes likelihood ratio thresholds for supporting or strong evidence.
Evidence considered
- MSH6 BS4 rule reviewed
Still missing
- Pedigree-level non-segregation data with Bayes likelihood ratio
Sources
BP5 No tumor data were identified showing mismatch repair findings inconsistent with MSH6 involvement, so BP5 cannot be applied. Details ▾Hide ▴
Rule
Tumor evidence inconsistent with the gene demonstrating genetic variation, with supporting or strong strength based on amount of evidence.
Evidence considered
- MSH6 BP5 rule reviewed
Still missing
- Tumor MSI/IHC findings inconsistent with MSH6
- BRAF V600E or MLH1 methylation data if relevant
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks PS4 not applicable
Sources
PM1 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks PM1 not applicable
- No hotspot row found in reviewed hotspot material
Sources
PM4 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks PM4 not applicable
Sources
PM6 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks PM6 not applicable
Sources
PP2 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks PP2 not applicable
Sources
PP5 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks PP5 not applicable
Sources
BP1 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks BP1 not applicable
Sources
BP2 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks BP2 not applicable
Sources
BP3 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks BP3 not applicable
Sources
BP6 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks BP6 not applicable
Sources
BP7 N/AThis is a missense variant, not a synonymous or qualifying intronic variant, so BP7 does not apply. Details ▾Hide ▴
Rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic).
Evidence considered
- Variant protein consequence p.Gly289Asp
Sources
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.866G>A
- Protein (HGVS p.)
- NP_000170.1:p.(Gly289Asp)
- GRCh38
- chr2:47798849 G>A
- GRCh37
- chr2:48025988 G>A
- ClinVar
- 627661, 89572
Gene diagram
Every interpreted variant in MSH6, mapped onto the exon structure of NM_000179.3. Select a row to find it on the plot.
MSH6NM_000179.3
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 MSH6
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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
350 / 1,614,052 alleles
AF 0.000217 · 0 homozygotes · FAF 0.000246
gnomAD v2.1
26 / 282,558 alleles
AF 9.2e-05 · 0 homozygotes · FAF 0.000124
By genetic ancestry
gnomAD v4.1
AF 0.00022 · 350 / 1,614,052 alleles · 0 hom · FAF 0.00025
| Remaining individuals25 / 62,486 | 0.0004 |
| European (non-Finnish)320 / 1,180,044 | 0.00027 |
| African/African American5 / 74,920 | 6.7e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 9.2e-05 · 26 / 282,558 alleles · 0 hom · FAF 0.00012
| European (non-Finnish)25 / 128,956 | 0.00019 |
| African/African American1 / 24,928 | 4e-05 |
0 alternate alleles recorded in 6 other groups: 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= 0.000216846; MAF= 0.02168%, 350/1614052 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00040009; MAF= 0.04001%, 25/62486 alleles, homozygotes = 0); grpmax FAF= 0.00024593.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 9.20165e-05; MAF= 0.00920%, 26/282558 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000193865; MAF= 0.01939%, 25/128956 alleles, homozygotes = 0); grpmax FAF= 0.00012357.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.272
- BayesDel
- -0.256
How the predictions were used
BP4 SupportingComputational evidence supports a benign interpretation. For this MSH6 missense variant, the HCI prior probability is 0.0021, which is below the BP4 threshold of 0.11. Additional predictors do not suggest a damaging effect, with REVEL 0.272, BayesDel -0.256015, and SpliceAI max delta 0.01 indicating no significant splice impact. Details ▾Hide ▴
Rule
Missense variant with HCI-prior probability of pathogenicity <0.11.
Evidence considered
- HCI prior 0.0021
- REVEL 0.272
- BayesDel -0.256015
- SpliceAI max delta 0.01
Sources
PP3 Computational evidence does not support pathogenicity under the MSH6 missense PP3 rule. The HCI prior probability is 0.0021, which is below the PP3 thresholds of >0.68 for supporting and >0.81 for moderate evidence. SpliceAI also does not predict a splice defect, with a max delta score of 0.01, below the non-canonical splice threshold of 0.2. Details ▾Hide ▴
Rule
Missense variant with HCI prior probability for pathogenicity >0.68 (supporting) or >0.81 (moderate), or predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score ≥0.2.
Evidence considered
- HCI prior 0.0021
- SpliceAI max delta 0.01
Sources
BP7 N/AThis is a missense variant, not a synonymous or qualifying intronic variant, so BP7 does not apply. Details ▾Hide ▴
Rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic).
Evidence considered
- Variant protein consequence p.Gly289Asp
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.272. BayesDel score = -0.256015. HCI prior probability for pathogenicity = 0.0021. MAPP score = 3.78. Custom PP2 score = 0.001.
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 16010685 ↗Rapid recognition of aberrant dHPLC elution profiles using the Transgenomic Navigator software.Colley J et al. · 2005No 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.Richards S et al. · 2015No paper-specific finding is recorded.
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PMID 26898890 ↗Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations.Caminsky NG et al. · 2016No paper-specific finding is recorded.
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PMID 18269114 ↗Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts.Devlin LA et al. · 2008No paper-specific finding is recorded.
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PMID 25394175 ↗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. · 2015No paper-specific finding is recorded.
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PMID 26580448 ↗Germline Mutations in Predisposition Genes in Pediatric Cancer.Zhang J et al. · 2015No paper-specific finding is recorded.
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PMID 27997549 ↗Enrichment of Targetable Mutations in the Relapsed Neuroblastoma Genome.Padovan-Merhar OM et al. · 2016No paper-specific finding is recorded.
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PMID 28767289 ↗Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma.Shindo K et al. · 2017No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
350 / 1,614,052 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
3 Uncertain significance · 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/1578294885
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/627661/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48025988-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47798849-G-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.866G…
- OncoKB ↗www.oncokb.org/gene/MSH6/G289D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.866G%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= 0.000216846; MAF= 0.02168%, 350/1614052 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00040009; MAF= 0.04001%, 25/62486 alleles, homozygotes = 0); grpmax FAF= 0.00024593.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 9.20165e-05; MAF= 0.00920%, 26/282558 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000193865; MAF= 0.01939%, 25/128956 alleles, homozygotes = 0); grpmax FAF= 0.00012357.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 627661)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.272. BayesDel score = -0.256015. HCI prior probability for pathogenicity = 0.0021. MAPP score = 3.78. Custom PP2 score = 0.001.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH6, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial 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.