About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.1054G>A, p.(Val352Ile)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
HCI prior probability for pathogenicity 0.0007 falls below the InSiGHT MSH6 VCEP BP4_Supporting threshold of <0.11. SpliceAI max delta score 0.00 confirms no predicted splicing impact. REVEL score 0.216 and BayesDel score -0.443 are also consistent with a benign computational profile.
Recorded classification: Uncertain significance
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 was evaluated deterministically with applied criteria: BP4 supporting benign; no rule matched the adjudicated criteria.
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
150 / 1,614,044 alleles
gnomAD v4.1: 150 / 1,614,044 alleles. Recorded AF 9.29343e-05. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.4311e-05; MAF= 0.00743%, 21/282596 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000293964; MAF= 0.02940%, 9/30616 alleles, homozygotes = 1); grpmax FAF= 0.00015255.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00021715526601520088, 4/18420 alleles, homozygotes = 0).
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
14 reported laboratory submissions
9 Likely benign · 4 Uncertain significance · 1 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
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52274944, n = 3 times).
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.
29 criteria with recorded statuses: 1 met · 5 not met · 9 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000179.3(MSH6):c.1054G>A (p.Val352Ile) is a missense substitution in exon 4 of MSH6.
This variant has been observed in gnomAD v4.1 at an overall allele frequency of 0.000093 (150/1,614,044 alleles, 1 homozygote), with a grpmax filtering allele frequency of 0.000199 (0.0199%). In gnomAD v2.1 the variant is present at an allele frequency of 0.000074 (21/282,596 alleles, 1 homozygote). It is absent from gnomAD-Canada v1.0.
The gnomAD v4.1 grpmax FAF (0.000199) is below the InSiGHT MSH6 VCEP BS1 threshold of ≥0.00022 and far below the BA1 threshold of ≥0.0022, so neither allele-frequency-based benign criterion is met. The overall allele frequency also exceeds the PM2 supporting threshold of <0.00002, so PM2 is not met.
Computational predictors strongly favor a benign effect: the HCI prior probability for pathogenicity is 0.0007 (far below the BP4_Supporting threshold of <0.11), SpliceAI predicts no splicing impact (max delta 0.00), REVEL score is 0.216, and BayesDel score is -0.443.
The variant was detected as a somatic finding in a tumor from a suspected Lynch syndrome patient (PMID:25111426), where it was classified as class 2 (likely not pathogenic) with 34% variant allele frequency, retention of heterozygosity, and normal MMR protein expression by IHC. This somatic observation is consistent with a benign or low-impact variant but does not independently meet any VCEP criterion in a germline context.
In ClinVar, this variant is reported as Likely benign by 9 clinical laboratories, Uncertain significance by 4, and Benign by 1 (ClinVar Variation ID: 182617). The InSiGHT expert panel has not issued a classification for this variant.
No pathogenic or likely pathogenic missense variants at the same amino acid residue (Val352) were identified in InSiGHT VCEP records, so PM5 cannot be assessed.
Applying the InSiGHT MSH6 VCEP version 2.0.0 combining rules: BP4_Supporting is the only criterion met. With a single benign supporting criterion, neither the Likely Benign threshold (≥2 benign supporting per Rule 19, or 1 benign strong + 1 benign supporting per Rule 18) nor any pathogenic threshold is reached. The variant is classified as Uncertain Significance.
No criteria match.
Met · 1
BP4 SupportingHCI prior probability for pathogenicity 0.0007 falls below the InSiGHT MSH6 VCEP BP4_Supporting threshold of <0.11. SpliceAI max delta score 0.00 confirms no predicted splicing impact. REVEL score 0.216 and BayesDel score -0.443 are also consistent with a benign computational profile. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0007 (<0.11 threshold for BP4_Supporting). SpliceAI max delta = 0.00. REVEL = 0.216. BayesDel = -0.443.
Sources
Not met · 5 · evaluated, threshold not reached
PS3 No calibrated functional assay data available in the VCEP MMR functional assay documentation. In silico scores (REVEL 0.216, BayesDel -0.443, HCI prior 0.0007) do not support a pathogenic functional effect. Details ▾Hide ▴
Evidence considered
- REVEL score 0.216 is not predictive of pathogenicity. BayesDel score -0.443 favors benign. HCI prior 0.0007 is strongly benign-leaning. No variant-specific functional assay in VCEP MMR functional assay documentation.
Still missing
- No calibrated functional assay (odds ratio) available for this variant.
Sources
revelbayesdelhci_prior
PM2 gnomAD v4.1 allele frequency 0.000093 (150/1,614,044 alleles) exceeds the InSiGHT MSH6 VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles). The variant also has one homozygote in gnomAD v4.1 and one homozygote in gnomAD v2.1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 9.29e-05 (150/1
- 614
- 044 alleles
- 1 homozygote). gnomAD v2.1 AF = 7.43e-05 (21/282
- 596 alleles
- 1 homozygote). gnomAD-Canada absent.
Sources
PP3 HCI prior probability for pathogenicity 0.0007 is far below the InSiGHT MSH6 VCEP PP3_Moderate threshold (>0.81) and PP3_Supporting threshold (>0.68). SpliceAI max delta score 0.00 is below the PP3_Supporting threshold for non-canonical splice variants (≥0.2). REVEL score 0.216 and BayesDel score -0.443 do not support a pathogenic prediction. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0007 (threshold >0.68 for PP3_Supporting). SpliceAI max delta = 0.00 (threshold ≥0.2). REVEL = 0.216 (not predictive). BayesDel = -0.443 (benign-leaning).
Sources
BA1 gnomAD v4.1 grpmax filtering allele frequency 0.000199 (0.0199%) is below the InSiGHT MSH6 VCEP BA1 threshold of ≥0.0022 (0.22%). Details ▾Hide ▴
BS1 gnomAD v4.1 grpmax filtering allele frequency 0.000199 (0.0199%) is slightly below the InSiGHT MSH6 VCEP BS1 threshold of ≥0.00022 (0.022%). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 0.00019901 (threshold ≥0.00022). Misses BS1 threshold by a factor of ~1.1.
Still missing
- grpmax FAF is very close to the BS1 threshold
- borderline call.
Sources
Not assessed · 9 · no assessment recorded
PS1 No previously classified pathogenic variant encoding the same amino acid change (Val352Ile) via a different nucleotide change was identified in InSiGHT MSH6 VCEP records. Details ▾Hide ▴
Evidence considered
- No same-amino-acid comparator variant found in VCEP pilot variants or ClinVar expert panel records.
Still missing
- No VCEP-classified pathogenic missense variant at codon 352.
PS2 No de novo observation data available for this variant. Details ▾Hide ▴
Still missing
- No de novo reports identified in ClinVar
- literature
- or other sources.
PM5 No pathogenic or likely pathogenic missense variant at the same amino acid residue (Val352) identified in InSiGHT MSH6 VCEP records. PM5 candidate search returned zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants found. No VCEP-classified pathogenic missense at codon 352.
Still missing
- No VCEP-classified pathogenic/likely pathogenic missense variants at codon 352.
Sources
pm5_candidates
PP1 No co-segregation data available for this variant. Details ▾Hide ▴
Still missing
- No pedigree or co-segregation data available.
PP4 No tumor phenotype data (MSI status, MMR IHC) specific to this germline variant available in evidence sources. Details ▾Hide ▴
Still missing
- No MSI status or MMR IHC data for tumors from germline carriers of this variant.
BS2 No trans co-occurrence data with a known pathogenic MSH6 variant available. Details ▾Hide ▴
Still missing
- No phased trans co-occurrence data available.
BS3 No calibrated functional assay data available for this variant in the VCEP MMR functional assay documentation. No variant-specific functional studies identified in the literature. Details ▾Hide ▴
Evidence considered
- VCEP functional assay spreadsheet (Functional-assay-SVI-documentation-MMR.xlsx) does not include c.1054G>A / p.Val352Ile.
Still missing
- No calibrated functional assay (odds ratio) data available.
BS4 No co-segregation data available for this variant. Details ▾Hide ▴
Still missing
- No pedigree or co-segregation data available.
BP5 No tumor phenotype data (MSS/MSI status, MMR IHC) from germline carriers of this variant available. A somatic observation in a tumor with normal MMR protein expression was reported (PMID:25111426) but does not independently meet BP5 criteria in a germline context. Details ▾Hide ▴
Evidence considered
- Somatic observation in tumor with normal MMR IHC (PMID:25111426
- class 2) noted but insufficient for germline BP5.
Still missing
- No germline tumor phenotype data meeting VCEP BP5 criteria.
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense substitution (p.Val352Ile); does not meet InSiGHT MSH6 VCEP PVS1 criteria, which require nonsense/frameshift PTC ≤ codon 1341, canonical splice site alteration, large genomic alteration, or confirmed splicing aberration. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant
- canonical splice variant
- or initiation codon variant.
Sources
pvs1_gene_contextpvs1_variant_assessment
PS4 VCEPCriterion not for use per InSiGHT MSH6 VCEP specifications. Details ▾Hide ▴
No further detail was recorded.
PM1 VCEPCriterion not for use per InSiGHT MSH6 VCEP specifications. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASubstitution variant; PM3 assessment requires specific trans configuration data relevant to recessive conditions. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPSubstitution variant; PM4 applies to non-in-frame deletions/insertions causing protein length change. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPCriterion not for use per InSiGHT MSH6 VCEP specifications. Details ▾Hide ▴
No further detail was recorded.
PP2 VCEPCriterion not for use per InSiGHT MSH6 VCEP specifications. Details ▾Hide ▴
No further detail was recorded.
PP5 VCEPCriterion not for use per InSiGHT MSH6 VCEP specifications. InSiGHT expert panel has not classified this variant. Details ▾Hide ▴
No further detail was recorded.
BP1 VCEPCriterion not for use per InSiGHT MSH6 VCEP specifications. Details ▾Hide ▴
No further detail was recorded.
BP2 VCEPCriterion not for use per InSiGHT MSH6 VCEP specifications. Details ▾Hide ▴
No further detail was recorded.
BP3 VCEPSubstitution variant; BP3 applies to in-frame deletions/insertions. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPCriterion not for use per InSiGHT MSH6 VCEP specifications. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AMissense substitution (p.Val352Ile); BP7 requires a synonymous (silent) or intronic variant at or beyond -21/+7. Details ▾Hide ▴
No further detail was recorded.
PS5 N/ACriterion not defined in the InSiGHT MSH6 VCEP framework. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.1054G>A
- Protein (HGVS p.)
- NP_000170.1:p.(Val352Ile)
- GRCh38
- chr2:47799037 G>A
- GRCh37
- chr2:48026176 G>A
- ClinVar
- 1929998, 182617
- COSMIC
- COSV52274944
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
150 / 1,614,044 alleles
AF 9.29e-05 · 1 homozygotes · FAF 0.000199
gnomAD v2.1
21 / 282,596 alleles
AF 7.43e-05 · 1 homozygotes · FAF 0.000153
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 9.3e-05 · 150 / 1,614,044 alleles · 1 hom · FAF 0.0002
| Amish5 / 912 | 0.0055 |
| South Asian26 / 91,092 | 0.000291 hom |
| European (non-Finnish)112 / 1,180,022 | 9.5e-05 |
| Remaining individuals5 / 62,486 | 8e-05 |
| African/African American2 / 74,936 | 2.7e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, European (Finnish), East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 7.4e-05 · 21 / 282,596 alleles · 1 hom · FAF 0.00015
| South Asian9 / 30,616 | 0.000291 hom |
| European (non-Finnish)11 / 128,944 | 8.5e-05 |
| African/African American1 / 24,956 | 4e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, 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= 9.29343e-05; MAF= 0.00929%, 150/1614044 alleles, homozygotes = 1) and has highest observed frequency in the Amish population (AF= 0.00548246; MAF= 0.54825%, 5/912 alleles, homozygotes = 0); grpmax FAF= 0.00019901.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.4311e-05; MAF= 0.00743%, 21/282596 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000293964; MAF= 0.02940%, 9/30616 alleles, homozygotes = 1); grpmax FAF= 0.00015255.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00021715526601520088, 4/18420 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.216
- BayesDel
- -0.443
How the predictions were used
BP4 SupportingHCI prior probability for pathogenicity 0.0007 falls below the InSiGHT MSH6 VCEP BP4_Supporting threshold of <0.11. SpliceAI max delta score 0.00 confirms no predicted splicing impact. REVEL score 0.216 and BayesDel score -0.443 are also consistent with a benign computational profile. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0007 (<0.11 threshold for BP4_Supporting). SpliceAI max delta = 0.00. REVEL = 0.216. BayesDel = -0.443.
Sources
PP3 HCI prior probability for pathogenicity 0.0007 is far below the InSiGHT MSH6 VCEP PP3_Moderate threshold (>0.81) and PP3_Supporting threshold (>0.68). SpliceAI max delta score 0.00 is below the PP3_Supporting threshold for non-canonical splice variants (≥0.2). REVEL score 0.216 and BayesDel score -0.443 do not support a pathogenic prediction. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0007 (threshold >0.68 for PP3_Supporting). SpliceAI max delta = 0.00 (threshold ≥0.2). REVEL = 0.216 (not predictive). BayesDel = -0.443 (benign-leaning).
Sources
BP7 N/AMissense substitution (p.Val352Ile); BP7 requires a synonymous (silent) or intronic variant at or beyond -21/+7. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.216. BayesDel score = -0.442852. HCI prior probability for pathogenicity = 0.0007. MAPP score = 2.28. Custom PP2 score = 0.001.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
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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.This is the ACMG/AMP 2015 standards and guidelines for sequence variant interpretation. NM_000179.3:c.1054G>A was not identified in this paper.Does not name this variant
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Describes a standardized DNA variant scoring system (Karbassi et al., 2015). NM_000179.3:c.1054G>A was not identified in this paper.Does not name this variant
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PMID 28135145 ↗Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.Yurgelun MB et al. · 2017Reports germline cancer susceptibility gene mutations in individuals with colorectal cancer (Yurgelun et al., 2017). NM_000179.3:c.1054G>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.National Society of Genetic Counselors recommendations on genetic cancer risk assessment and counseling. NM_000179.3:c.1054G>A was not identified in the abstract of this paper.Does not name this variant
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PMID 23535968 ↗Informing family members of individuals with Lynch syndrome: a guideline for clinical geneticists.Guideline for informing family members of individuals with Lynch syndrome. NM_000179.3:c.1054G>A was not identified in the abstract of this paper.Does not name this variant
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PMID 25111426 ↗Somatic aberrations of mismatch repair genes as a cause of microsatellite-unstable cancers.Geurts-Giele WR et al. · 2014c.1054G>A (p.Val352Ile) reported in Supplementary Table as a somatic MSH6 variant in a tumor from a suspected Lynch syndrome patient. The variant was classified as class 2 (likely not pathogenic) with 34% variant allele frequency and retention of heterozygosity (ROH). The tumor showed no deficient MMR protein by immunohistochemistry.Names this variant
Quoted passage
MSH6: c.1054G>A; p.V352I / 2 / 34% (67/200) / ROH / no deficient MMR protein
Supplementary Table (lines 1625-1631 of full text), listing somatic MMR gene variants identified in tumors of sLS patients
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PMID 25186627 ↗Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.Tung N et al. · 2015Reports frequency of mutations in individuals with breast cancer referred for BRCA1/2 testing using a 25-gene panel (Tung et al., 2015). NM_000179.3:c.1054G>A was not identified in the abstract of this paper.Does not name this variant
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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. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment (Hampel et al., 2015). NM_000179.3:c.1054G>A was not identified in this paper.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria (Nykamp et al., 2017). NM_000179.3:c.1054G>A was not identified in the abstract of 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
150 / 1,614,044 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
9 Likely benign · 4 Uncertain significance · 1 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/182617/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48026176-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47799037-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47799037-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.1054…
- OncoKB ↗www.oncokb.org/gene/MSH6/V352I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124990044
- 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= 9.29343e-05; MAF= 0.00929%, 150/1614044 alleles, homozygotes = 1) and has highest observed frequency in the Amish population (AF= 0.00548246; MAF= 0.54825%, 5/912 alleles, homozygotes = 0); grpmax FAF= 0.00019901.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.4311e-05; MAF= 0.00743%, 21/282596 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000293964; MAF= 0.02940%, 9/30616 alleles, homozygotes = 1); grpmax FAF= 0.00015255.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00021715526601520088, 4/18420 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Uncertain significance (4 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 182617)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.216. BayesDel score = -0.442852. HCI prior probability for pathogenicity = 0.0007. MAPP score = 2.28. 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 previously been reported in somatic cancers (COSMIC; COSV52274944, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.