About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.533G>T, p.(Arg178Leu)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
The variant is extremely rare in gnomAD v4.1 with an allele frequency of 1.24e-6 (2/1,614,132 alleles), which is below the VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). Absent in gnomAD-Canada.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
The HCI prior probability for pathogenicity is 0.0003 for p.Arg178Leu in MSH6, which is well below the VCEP BP4_Supporting threshold of <0.11. This is further supported by a REVEL score of 0.084, BayesDel score of -0.372, and SpliceAI max delta score of 0.00, all consistent with a benign computational profile.
Recorded classification: Not classified
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 Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; maps to Uncertain Significance - Conflicting Evidence.
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
2 / 1,614,132 alleles
gnomAD v4.1: 2 / 1,614,132 alleles. Recorded AF 1.23906e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95393e-06; MAF= 0.00080%, 2/251448 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15233e-05; MAF= 0.00615%, 1/16254 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
6 reported laboratory submissions
3 Uncertain significance · 1 Likely benign · 1 Benign · 1 Uncertain Significance. 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. 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.
27 criteria with recorded statuses: 2 met · 14 not met · 0 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
c.533G>T (p.Arg178Leu) is a missense variant in exon 3 of MSH6.
The variant is extremely rare in population databases (gnomAD v4.1 allele frequency = 1.24e-6; 2/1,614,132 alleles, 0 homozygotes), meeting PM2_Supporting per the InSiGHT MSH6 VCEP threshold of <0.00002.
Multiple lines of computational evidence support a benign effect: HCI prior probability for pathogenicity = 0.0003 (meeting BP4_Supporting threshold <0.11), REVEL score = 0.084, BayesDel score = -0.372, and SpliceAI max delta = 0.00.
In ClinVar (Variation ID 483842), the variant is classified as Uncertain Significance by the majority of clinical laboratories (3 VUS, 1 Likely Benign, 1 Benign), with review status 'criteria provided, single submitter' and no expert panel review.
No variant-specific functional studies (PS3/BS3), segregation data (PP1/BS4), tumor phenotype data (PP4/BP5), de novo observations (PS2), or pathogenic comparator variants at the same residue (PM5/PS1) were identified.
Applying the InSiGHT MSH6 VCEP v2.0.0 combining rules: one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4_Supporting) yields conflicting evidence, classifying this variant as Uncertain Significance (Rule 31: >=1 Benign Supporting AND >=1 Pathogenic Supporting).
No criteria match.
Met · 2
PM2 SupportingThe variant is extremely rare in gnomAD v4.1 with an allele frequency of 1.24e-6 (2/1,614,132 alleles), which is below the VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). Absent in gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 1.23906e-6 (2/1
- 614
- 132 alleles
- 0 homozygotes)
- highest subpopulation: Middle Eastern AF = 0.000165 (1/6
- 062). gnomAD-Canada: absent. Both well below the VCEP PM2_Supporting threshold of 0.00002.
Sources
BP4 SupportingThe HCI prior probability for pathogenicity is 0.0003 for p.Arg178Leu in MSH6, which is well below the VCEP BP4_Supporting threshold of <0.11. This is further supported by a REVEL score of 0.084, BayesDel score of -0.372, and SpliceAI max delta score of 0.00, all consistent with a benign computational profile. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.0003 (<0.11 = BP4_Supporting). REVEL = 0.084 (benign range). BayesDel = -0.372 (benign range). SpliceAI max delta = 0.00 (no predicted splicing impact).
Sources
Not met · 14 · evaluated, threshold not reached
PS1 No alternative nucleotide change encoding p.Arg178Leu has been previously classified as Pathogenic or Likely Pathogenic by the InSiGHT VCEP. The variant is absent from the VCEP pilot variants spreadsheet and no ClinVar expert panel submissions exist for this residue. Details ▾Hide ▴
Evidence considered
- VCEP pilot variants spreadsheet: no match for c.533 or R178L. ClinVar variation ID 483842: no expert panel classification
- no alternative nucleotide change at codon 178 classified as Pathogenic.
Still missing
- No known pathogenic comparator with same amino acid change (R178L) from a different nucleotide substitution.
Sources
clinvar ↗vcep_vcep_pilot_variants_mmr
PS2 No de novo observations are documented for this variant. No publications or curated databases report de novo occurrence of c.533G>T (p.Arg178Leu) with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- ClinVar submission audit: zero criterion-lead submissions for de novo. No de novo reports in any reviewed publication.
Still missing
- No de novo testing data available.
Sources
PS3 No variant-specific calibrated functional assay data are available for p.Arg178Leu. The InSiGHT MMR functional assay SVI documentation does not include this variant. OncoKB reports 'Unknown Oncogenic Effect' with no curated functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional evidence. VCEP Functional-assay-SVI-documentation-MMR.xlsx: no entry for c.533G>T or p.Arg178Leu.
Still missing
- No functional assay data (MMR activity
- expression
- splicing) available for this variant.
Sources
oncokb ↗vcep_functional_assay_svi_documentation_mmr
PM5 No different missense variant at amino acid residue Arg178 has been classified as Pathogenic or Likely Pathogenic by the InSiGHT VCEP. The PM5 candidates search returned zero same-residue comparator variants. Without a pathogenic comparator at this residue, PM5 cannot be applied. Details ▾Hide ▴
Evidence considered
- PM5 candidates query: 0 same-residue candidates at Arg178. No ClinVar expert panel classifications for any missense change at codon 178.
Still missing
- No known pathogenic missense comparator at Arg178.
Sources
pm5_candidatesclinvar ↗
PP1 No co-segregation data are available for c.533G>T (p.Arg178Leu). No published pedigrees or Bayes likelihood ratio analyses have been performed for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data in any curated database or reviewed publication.
Still missing
- No pedigree or co-segregation analysis available.
PP3 The HCI prior probability for pathogenicity is 0.0003 for p.Arg178Leu in MSH6, which is well below the VCEP PP3_Supporting threshold (>0.68). SpliceAI delta score is 0.00, confirming no predicted splicing impact. REVEL score is 0.084 and BayesDel is -0.372, both consistent with a benign in silico profile. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.0003 (thresholds: >0.81 = PP3_Moderate
- >0.68 = PP3_Supporting). SpliceAI max delta = 0.00. REVEL = 0.084. BayesDel = -0.372375.
Sources
PP4 No tumor phenotype data are available for this variant. No reports of MSI-H tumors, MMR protein expression loss, or other LS-spectrum tumor characteristics in carriers of c.533G>T have been identified. Details ▾Hide ▴
Evidence considered
- No tumor MSI/IHC data available in ClinVar
- publications
- or curated databases.
Still missing
- No tumor pathology data (MSI status
- IHC) for variant carriers.
BA1 The gnomAD v4.1 allele frequency is 1.24e-6 (0.000124%), which is far below the VCEP BA1 stand-alone threshold of >=0.0022 (0.22%). The variant is not a founder pathogenic variant. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 1.23906e-6 (0.000124%)
- well below BA1 threshold of 0.22%.
Sources
BS1 The gnomAD v4.1 allele frequency is 1.24e-6 (0.000124%), which is below the VCEP BS1_Strong threshold range of >=0.00022 (0.022%) to <0.0022 (0.22%). The highest subpopulation frequency (Middle Eastern, AF = 0.000165) also falls below this threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 1.23906e-6
- highest subpop (Middle Eastern) AF = 0.000165. Both below BS1 lower bound of 0.00022.
Sources
BS2 No evidence of co-occurrence in trans with a known pathogenic MSH6 variant has been reported. No individual with biallelic MSH6 variants has been identified with CRC after age 45 and absence of CMMRD features. Details ▾Hide ▴
Evidence considered
- No trans co-occurrence data reported in any database or publication.
Still missing
- No phase-confirmed trans observations available.
BS3 No variant-specific functional studies demonstrating benign effect are available for p.Arg178Leu. The InSiGHT MMR functional assay SVI documentation does not include this variant, and no calibrated functional odds for pathogenicity can be calculated. Details ▾Hide ▴
Evidence considered
- VCEP Functional-assay-SVI-documentation-MMR.xlsx: no entry for c.533G>T or p.Arg178Leu. No calibrated functional odds data available.
Still missing
- No MMR functional assay data available for this variant.
Sources
vcep_functional_assay_svi_documentation_mmr
BS4 No segregation data are available to assess lack of co-segregation with disease. No pedigree analysis with Bayes likelihood ratio has been performed for this variant. Details ▾Hide ▴
Evidence considered
- No segregation or lack-of-segregation data available.
Still missing
- No pedigree data for co-segregation or lack-of-segregation analysis.
BP5 No tumor data are available to apply BP5. No reports of MSS tumors, BRAF V600E mutations, or MLH1 methylation in tumors from carriers of this variant were identified. Details ▾Hide ▴
Evidence considered
- No tumor pathology data (MSS status
- BRAF
- MLH1 methylation) available for variant carriers.
Still missing
- No tumor data to support BP5.
PS5 PS5 is not defined in the MSH6 VCEP criteria set (the companion criterion BP6 is explicitly Not Applicable per VCEP). No reputable source has reported this variant as Pathogenic. The aggregate ClinVar classification is Uncertain Significance (3 clinical laboratories VUS, 1 LB, 1 B). Details ▾Hide ▴
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. c.533G>T (p.Arg178Leu) is a missense substitution that does not introduce a premature termination codon, affect a canonical splice site, or involve the initiation codon. The MSH6 VCEP PVS1 Decision Tree does not apply to missense variants. Details ▾Hide ▴
Evidence considered
- Missense variant (p.Arg178Leu) in exon 3
- does not meet any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798) or the MSH6 VCEP PVS1 rules.
Sources
pvs1_variant_assessmentpvs1_gene_context
PS4 VCEPPS4 is designated as Not Applicable by the MSH6 VCEP (InSiGHT Hereditary Colorectal Cancer/Polyposis EP Specifications v2.0.0). Case-control study data are not used for MSH6 variant classification under this framework. Details ▾Hide ▴
PM1 VCEPPM1 is designated as Not Applicable by the MSH6 VCEP. The InSiGHT EP does not apply the mutational hotspot criterion for MSH6 variant classification. Details ▾Hide ▴
PM6 VCEPPM6 is designated as Not Applicable by the MSH6 VCEP. De novo evidence is adjudicated under PS2 in this framework. Details ▾Hide ▴
PP2 VCEPPP2 is designated as Not Applicable by the MSH6 VCEP. The criterion for low rate of benign missense variation does not apply per the InSiGHT EP specifications. Details ▾Hide ▴
PP5 VCEPPP5 is designated as Not Applicable by the MSH6 VCEP. The InSiGHT EP does not use the 'reputable source' criterion for pathogenic classification. Details ▾Hide ▴
BP1 VCEPBP1 is designated as Not Applicable by the MSH6 VCEP. The criterion for missense variants in genes where only LOF causes disease does not apply per the InSiGHT EP specifications. Details ▾Hide ▴
BP2 VCEPBP2 is designated as Not Applicable by the MSH6 VCEP. Details ▾Hide ▴
BP3 VCEPIn-frame insertions/deletions in repetitive regions without known function are not applicable to this missense substitution variant. Details ▾Hide ▴
Evidence considered
- Variant type is substitution (missense)
- not an in-frame indel in a repetitive region.
BP6 VCEPBP6 is designated as Not Applicable by the MSH6 VCEP. The InSiGHT EP does not use the 'reputable source' criterion for benign classification. Details ▾Hide ▴
Evidence considered
- VCEP specification: BP6 applicability = Not Applicable for this VCEP.
Sources
BP7 N/ABP7 is applicable only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. c.533G>T is a missense variant (p.Arg178Leu) and does not meet BP7 criteria. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Arg178Leu)
- not synonymous or intronic.
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.533G>T
- Protein (HGVS p.)
- NP_000170.1:p.(Arg178Leu)
- GRCh38
- chr2:47795969 G>T
- GRCh37
- chr2:48023108 G>T
- ClinVar
- 483842
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
2 / 1,614,132 alleles
AF 1.24e-06 · 0 homozygotes
gnomAD v2.1
2 / 251,448 alleles
AF 7.95e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,614,132 alleles · 0 hom
| Middle Eastern1 / 6,062 | 0.00016 |
| African/African American1 / 75,028 | 1.3e-05 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, European (non-Finnish).
gnomAD v2.1
AF 8e-06 · 2 / 251,448 alleles · 0 hom
| African/African American1 / 16,254 | 6.2e-05 |
| European (non-Finnish)1 / 113,732 | 8.8e-06 |
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= 1.23906e-06; MAF= 0.00012%, 2/1614132 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164962; MAF= 0.01650%, 1/6062 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95393e-06; MAF= 0.00080%, 2/251448 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15233e-05; MAF= 0.00615%, 1/16254 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.084
- BayesDel
- -0.372
How the predictions were used
BP4 SupportingThe HCI prior probability for pathogenicity is 0.0003 for p.Arg178Leu in MSH6, which is well below the VCEP BP4_Supporting threshold of <0.11. This is further supported by a REVEL score of 0.084, BayesDel score of -0.372, and SpliceAI max delta score of 0.00, all consistent with a benign computational profile. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.0003 (<0.11 = BP4_Supporting). REVEL = 0.084 (benign range). BayesDel = -0.372 (benign range). SpliceAI max delta = 0.00 (no predicted splicing impact).
Sources
PP3 The HCI prior probability for pathogenicity is 0.0003 for p.Arg178Leu in MSH6, which is well below the VCEP PP3_Supporting threshold (>0.68). SpliceAI delta score is 0.00, confirming no predicted splicing impact. REVEL score is 0.084 and BayesDel is -0.372, both consistent with a benign in silico profile. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.0003 (thresholds: >0.81 = PP3_Moderate
- >0.68 = PP3_Supporting). SpliceAI max delta = 0.00. REVEL = 0.084. BayesDel = -0.372375.
Sources
BP7 N/ABP7 is applicable only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. c.533G>T is a missense variant (p.Arg178Leu) and does not meet BP7 criteria. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Arg178Leu)
- not synonymous or intronic.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.084. BayesDel score = -0.372375. HCI prior probability for pathogenicity = 0.0003. MAPP score = 1.62. Custom PP2 score = 0.001.
7 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
-
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.ACMG/AMP 2015 consensus guidelines for the interpretation of sequence variants. NM_000179.3:c.533G>T was not mentioned in this paper.Does not name this variant
-
PMID 31672839 ↗Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.Updated CAPS Consortium recommendations for pancreatic cancer surveillance in high-risk individuals, including those with Lynch syndrome. NM_000179.3:c.533G>T was not mentioned in this paper.Does not name this variant
-
PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004National Society of Genetic Counselors recommendations for cancer genetic risk assessment and counseling. NM_000179.3:c.533G>T was not mentioned in this paper.Does not name this variant
-
PMID 23535968 ↗Informing family members of individuals with Lynch syndrome: a guideline for clinical geneticists.Guideline for clinical geneticists on informing family members of individuals with Lynch syndrome. NM_000179.3:c.533G>T was not mentioned in this paper.Does not name this variant
-
PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG policy statement on updated recommendations for analysis and reporting of secondary findings in clinical genome-scale sequencing. NM_000179.3:c.533G>T was not mentioned in this paper.Does not name this variant
-
PMID 25452455 ↗Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines.Stoffel EM et al. · 2015ASCO clinical practice guideline endorsement of ESMO guidelines for familial risk-colorectal cancer. NM_000179.3:c.533G>T was not mentioned in this paper.Does not name this variant
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc refinement of ACMG-AMP variant classification criteria. NM_000179.3:c.533G>T was not mentioned in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,614,132 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
3 Uncertain significance · 1 Likely benign · 1 Benign · 1 Uncertain Significance
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/483842/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48023108-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47795969-G-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47795969-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.533G…
- OncoKB ↗www.oncokb.org/gene/MSH6/R178L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.533G%3ET
- 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= 1.23906e-06; MAF= 0.00012%, 2/1614132 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164962; MAF= 0.01650%, 1/6062 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95393e-06; MAF= 0.00080%, 2/251448 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15233e-05; MAF= 0.00615%, 1/16254 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 483842)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.084. BayesDel score = -0.372375. HCI prior probability for pathogenicity = 0.0003. MAPP score = 1.62. 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.