About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.1822A>G, p.(Ile608Val)
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. 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
BP4_supporting is met under the InSiGHT MSH6 VCEP v2.0: the HCI prior probability for pathogenicity is 0.0038, which is below the <0.11 threshold. Multiple independent in silico predictors support a benign interpretation: REVEL score 0.185 (low pathogenicity), BayesDel score -0.360 (benign), and SpliceAI max delta 0.01 (no predicted splicing impact).
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 v2.0 criteria-combination framework was evaluated deterministically with applied criteria: BP4 supporting; 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
100 / 1,614,126 alleles
gnomAD v4.1: 100 / 1,614,126 alleles. Recorded AF 6.1953e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.83724e-05; MAF= 0.00284%, 8/281964 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.43225e-05; MAF= 0.00543%, 7/128860 alleles, homozygotes = 0); grpmax FAF= 2.298e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
11 reported laboratory submissions
9 Uncertain significance · 1 Uncertain Significance · 1 Likely benign. 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, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 15 not met · 0 not assessed · 13 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:c.1822A>G (p.Ile608Val) is a missense variant in exon 4 of MSH6. Only one criterion is met: BP4_supporting based on an HCI prior probability of 0.0038 (<0.11), with concordant in silico predictions (REVEL 0.185, BayesDel -0.360, SpliceAI Δ=0.01). All other applicable criteria are not met, and no pathogenic criteria are met.
This variant has been observed in gnomAD v4.1 at a grpmax FAF of 6.393e-05 (100/1,614,126 alleles, 0 homozygotes), which is above the VCEP PM2_supporting threshold of 0.00002 but below the benign BA1 (0.0022) and BS1 (0.00022) thresholds. The variant is present at low frequency in population databases, consistent with a rare variant of uncertain significance.
This variant has been reported in ClinVar as Uncertain significance by 10 of 11 clinical submitters and as Likely benign by 1 submitter (ClinVar Variation ID: 182626). No expert panel classification exists, and the review status is 'criteria provided, single submitter.' The variant has not been reported in COSMIC.
No functional assay data are available for this variant in the InSiGHT MMR calibrated functional assay documentation. The variant was predicted to have 'no impact on MSH6' by the CoDP in silico tool (score 0.033; PMID:23621914), but this is computational prediction, not experimental functional evidence.
Overall, NM_000179.3:c.1822A>G (p.Ile608Val) is classified as a Variant of Uncertain Significance (VUS) under the InSiGHT MSH6 VCEP v2.0 framework. Only BP4_supporting is met; all other applicable criteria are not met. No pathogenic criteria are met, and no benign criteria beyond BP4_supporting apply.
No criteria match.
Met · 1
BP4 SupportingBP4_supporting is met under the InSiGHT MSH6 VCEP v2.0: the HCI prior probability for pathogenicity is 0.0038, which is below the <0.11 threshold. Multiple independent in silico predictors support a benign interpretation: REVEL score 0.185 (low pathogenicity), BayesDel score -0.360 (benign), and SpliceAI max delta 0.01 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.0038 (<0.11 threshold for BP4_supporting per VCEP)
- REVEL score = 0.185 (low)
- BayesDel score = -0.360
- SpliceAI max delta = 0.01 (no splicing impact)
Sources
Not met · 15 · evaluated, threshold not reached
PS1 No different underlying nucleotide change encoding the same amino acid substitution (p.Ile608Val) has been classified as Pathogenic or Likely Pathogenic by the InSiGHT MSH6 VCEP. The variant is absent from the VCEP pilot variants spreadsheet and no such comparator was identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No same-amino-acid comparator classified as Pathogenic by VCEP identified.
Sources
cspec ↗vcep_vcep_pilot_variants_mmr
PS2 No de novo observations were identified for NM_000179.3:c.1822A>G in the available evidence. The InSiGHT MSH6 VCEP requires de novo points derived from confirmed parentage in MMR-deficient tumors; zero de novo events are documented. Details ▾Hide ▴
Evidence considered
- No de novo events reported in ClinVar or literature for this variant.
Still missing
- No de novo data available.
Sources
PS3 No calibrated functional assay data exist for NM_000179.3:c.1822A>G (p.Ile608Val). The InSiGHT MMR functional assay SVI documentation does not include this variant. One publication (PMID:23621914) provided an in silico CoDP prediction score of 0.033, classifying it as having 'no impact on MSH6,' but in silico prediction does not constitute experimental functional evidence for PS3 under the VCEP framework. Details ▾Hide ▴
Evidence considered
- No variant-specific functional assay data available. In silico prediction alone does not satisfy PS3.
Still missing
- No functional assay data for this variant.
Sources
vcep_functional_assay_svi_documentation_mmrcspec ↗
PM2 PM2_supporting requires gnomAD v4 grpmax filtering allele frequency < 0.00002 (<1 in 50,000 alleles) per InSiGHT MSH6 VCEP. The observed grpmax FAF is 6.393e-05 (0.0064%), which exceeds the threshold. The variant is present in 100/1,614,126 alleles in gnomAD v4.1 and 8/281,964 alleles in gnomAD v2.1, indicating it is not absent or extremely rare. Details ▾Hide ▴
Evidence considered
- gnomAD v4 grpmax FAF = 6.393e-05
- above the VCEP PM2_supporting threshold of 0.00002.
Sources
PM5 PM5 requires a different missense change at the same amino acid residue (Ile608) classified as Pathogenic or Likely Pathogenic by the VCEP, AND PP3 must be supporting. PP3 is not met (HCI prior = 0.0038, well below the 0.68 threshold). Additionally, no Pathogenic/Likely Pathogenic same-residue comparator was identified in the VCEP pilot variants or ClinVar at Ile608. Details ▾Hide ▴
Evidence considered
- PP3 not supporting (HCI prior 0.0038)
- and no same-residue Pathogenic/Likely Pathogenic comparator identified.
Sources
PP1 No co-segregation data are available for NM_000179.3:c.1822A>G. The InSiGHT MSH6 VCEP requires a combined Bayes Likelihood Ratio from segregation analysis in pedigrees; no such data exist in the evidence. Details ▾Hide ▴
Evidence considered
- No segregation data available for this variant.
Still missing
- No co-segregation analysis performed.
Sources
PP3 PP3 requires HCI prior probability > 0.68 for supporting or > 0.81 for moderate per InSiGHT MSH6 VCEP. The HCI prior probability for p.Ile608Val is 0.0038, which is well below both thresholds. Additional in silico evidence confirms a benign profile: REVEL score 0.185, BayesDel score -0.360, SpliceAI max delta 0.01. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0038 (<0.68 threshold)
- REVEL = 0.185
- BayesDel = -0.360
- SpliceAI max delta = 0.01.
Sources
PP4 No tumor data (MSI status or MMR IHC) are available for patients carrying NM_000179.3:c.1822A>G. The InSiGHT MSH6 VCEP requires CRC/endometrial tumors with MSI-H and/or loss of MMR protein expression consistent with the variant location. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available for this variant.
Still missing
- No MSI or IHC data from patient tumors.
Sources
BA1 BA1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0022 (0.22%) per InSiGHT MSH6 VCEP. The observed grpmax FAF is 6.393e-05 (0.0064%), which is far below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4 grpmax FAF = 6.393e-05
- well below BA1 threshold of 0.0022.
Sources
BS1 BS1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.00022 (0.022%) and < 0.0022 per InSiGHT MSH6 VCEP. The observed grpmax FAF is 6.393e-05 (0.0064%), which is below the BS1 lower threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4 grpmax FAF = 6.393e-05
- below BS1 threshold of 0.00022.
Sources
BS2 No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without CMMRD features. The InSiGHT MSH6 VCEP requires confirmed phase through parental testing. Details ▾Hide ▴
Evidence considered
- No in trans co-occurrence data available.
Still missing
- No phase-confirmed co-occurrence observations.
Sources
BS3 No calibrated functional assay data demonstrate proficient MMR function (functional odds ≤ 0.05 for BS3_strong or ≤ 0.48 for BS3_supporting) for NM_000179.3:c.1822A>G. The InSiGHT MMR functional assay SVI documentation does not include this variant. The in silico CoDP score of 0.033 from PMID:23621914 predicts no impact but does not constitute a validated functional assay. Details ▾Hide ▴
Evidence considered
- No experimental functional assay data for this variant.
Still missing
- No calibrated functional assay performed.
Sources
vcep_functional_assay_svi_documentation_mmrcspec ↗
BS4 No lack-of-segregation data are available. The InSiGHT MSH6 VCEP requires combined Bayes Likelihood Ratio from pedigrees demonstrating absence of co-segregation. Details ▾Hide ▴
Evidence considered
- No segregation data — neither co-segregation nor lack of co-segregation.
Still missing
- No segregation analysis available.
Sources
BP5 No tumor data (MSS status or MMR IHC) are available for patients carrying NM_000179.3:c.1822A>G. The InSiGHT MSH6 VCEP requires CRC/endometrial tumors with MSS and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation in MSI-H tumors, to apply BP5. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available to assess BP5.
Still missing
- No tumor MSS/IHC data available.
Sources
BP7 BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7. NM_000179.3:c.1822A>G is a missense variant (p.Ile608Val) and does not meet the BP7 criteria. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous and intronic variants.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_000179.3:c.1822A>G is a missense substitution (p.Ile608Val) and does not fall into any PVS1 null-variant bucket per the InSiGHT MSH6 VCEP v2.0 framework (nonsense, frameshift, canonical splice, initiation codon, or exon-level deletion). Details ▾Hide ▴
Evidence considered
- Missense variant (p.Ile608Val)
- not a null variant covered by PVS1 rules.
Sources
pvs1_variant_assessmentcspec ↗
PS4 VCEPPS4 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework. Details ▾Hide ▴
PM1 VCEPPM1 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework. Details ▾Hide ▴
PM3 N/ASkipped per adjudication instructions — trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPSkipped per adjudication instructions — trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPPM6 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework. The VCEP notes that 'missense variant in a gene with low rate of benign missense changes does not apply' for MSH6. Details ▾Hide ▴
PP5 VCEPPP5 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework. The VCEP explicitly marks this criterion as 'Not Applicable for this VCEP' per ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework. The VCEP notes 'missense variant in a gene where only loss of function causes disease is not applicable' for MSH6. Details ▾Hide ▴
BP2 VCEPBP2 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework. Details ▾Hide ▴
BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions without known function; this is a missense substitution. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP3 is restricted to in-frame indels in repetitive regions.
Sources
BP6 VCEPBP6 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework. The VCEP explicitly marks this criterion as 'Not Applicable for this VCEP' per ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
PS5 N/APS5 is not included in the InSiGHT MSH6 VCEP v2.0 criteria set and is not applicable in this framework. Details ▾Hide ▴
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.1822A>G
- Protein (HGVS p.)
- NP_000170.1:p.(Ile608Val)
- GRCh38
- chr2:47799805 A>G
- GRCh37
- chr2:48026944 A>G
- ClinVar
- 1479218, 182626
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
100 / 1,614,126 alleles
AF 6.2e-05 · 0 homozygotes · FAF 6.39e-05
gnomAD v2.1
8 / 281,964 alleles
AF 2.84e-05 · 0 homozygotes · FAF 2.3e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-05 · 100 / 1,614,126 alleles · 0 hom · FAF 6.4e-05
| Remaining individuals7 / 62,490 | 0.00011 |
| European (non-Finnish)91 / 1,180,042 | 7.7e-05 |
| African/African American2 / 74,952 | 2.7e-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 2.8e-05 · 8 / 281,964 alleles · 0 hom · FAF 2.3e-05
| European (non-Finnish)7 / 128,860 | 5.4e-05 |
| European (Finnish)1 / 25,120 | 4e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.1953e-05; MAF= 0.00620%, 100/1614126 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000112018; MAF= 0.01120%, 7/62490 alleles, homozygotes = 0); grpmax FAF= 6.393e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.83724e-05; MAF= 0.00284%, 8/281964 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.43225e-05; MAF= 0.00543%, 7/128860 alleles, homozygotes = 0); grpmax FAF= 2.298e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.185
- BayesDel
- -0.360
How the predictions were used
BP4 SupportingBP4_supporting is met under the InSiGHT MSH6 VCEP v2.0: the HCI prior probability for pathogenicity is 0.0038, which is below the <0.11 threshold. Multiple independent in silico predictors support a benign interpretation: REVEL score 0.185 (low pathogenicity), BayesDel score -0.360 (benign), and SpliceAI max delta 0.01 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.0038 (<0.11 threshold for BP4_supporting per VCEP)
- REVEL score = 0.185 (low)
- BayesDel score = -0.360
- SpliceAI max delta = 0.01 (no splicing impact)
Sources
PP3 PP3 requires HCI prior probability > 0.68 for supporting or > 0.81 for moderate per InSiGHT MSH6 VCEP. The HCI prior probability for p.Ile608Val is 0.0038, which is well below both thresholds. Additional in silico evidence confirms a benign profile: REVEL score 0.185, BayesDel score -0.360, SpliceAI max delta 0.01. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0038 (<0.68 threshold)
- REVEL = 0.185
- BayesDel = -0.360
- SpliceAI max delta = 0.01.
Sources
BP7 BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7. NM_000179.3:c.1822A>G is a missense variant (p.Ile608Val) and does not meet the BP7 criteria. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous and intronic variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.185. BayesDel score = -0.360174. HCI prior probability for pathogenicity = 0.0038. MAPP score = 4.95. Custom PP2 score = 0.003.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
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PMID 22949379 ↗A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.Thompson BA et al. · 2013Describes a multifactorial likelihood model for MMR gene variant classification incorporating sequence bioinformatics and tumor characteristics. NM_000179.3:c.1822A>G (p.Ile608Val) 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.ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a general framework document and does not discuss NM_000179.3:c.1822A>G.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 for pathogenicity assessments in Mendelian disorders. NM_000179.3:c.1822A>G was not identified in this paper.Does not name this variant
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PMID 30374176 ↗Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.Tsai GJ et al. · 2019Reports outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. The abstract does not mention NM_000179.3:c.1822A>G or any specific MSH6 variant.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. · 2001Practice parameters for identification and testing of patients at risk for dominantly inherited colorectal cancer. This is a clinical guideline and does not discuss specific MSH6 variants.Does not name this variant
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PMID 20301390 ↗Lynch Syndrome.Adam MP et al. · 1993GeneReviews entry on Lynch Syndrome. This is a general clinical overview and does not discuss NM_000179.3:c.1822A>G specifically.Does not name this variant
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PMID 23621914 ↗CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein.Terui H et al. · 2013CoDP in silico prediction tool for MSH6 missense variants. p.Ile608Val was classified among 260 unclassified variants and assigned a joint score of 0.033, placing it in the category of 'variants with no impact on MSH6.' This is a computational prediction, not experimental functional data.Names this variant
Quoted passage
I608V 0.033
Results, Table 8: Classification results of UVs in MSH6 by CoDP
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PMID 23788249 ↗ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.ACMG recommendations for reporting incidental findings in clinical exome and genome sequencing. This is a policy statement and does not discuss specific MSH6 variants.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. This is a general methods paper and does not discuss NM_000179.3:c.1822A>G.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
100 / 1,614,126 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
9 Uncertain significance · 1 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/1578294885
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/182626/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48026944-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47799805-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47799805-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.1822…
- OncoKB ↗www.oncokb.org/gene/MSH6/I608V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.1822A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.1953e-05; MAF= 0.00620%, 100/1614126 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000112018; MAF= 0.01120%, 7/62490 alleles, homozygotes = 0); grpmax FAF= 6.393e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.83724e-05; MAF= 0.00284%, 8/281964 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.43225e-05; MAF= 0.00543%, 7/128860 alleles, homozygotes = 0); grpmax FAF= 2.298e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 182626)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.185. BayesDel score = -0.360174. HCI prior probability for pathogenicity = 0.0038. MAPP score = 4.95. Custom PP2 score = 0.003.
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.