About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.1483C>T, p.(Arg495Ter)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic 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. 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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
NM_000179.2:c.1483C>T is a nonsense variant that introduces a premature termination codon (p.Arg495Ter) at codon 495, which is well below the VCEP threshold of codon 1341 for MSH6. Under the ClinGen InSiGHT MSH6 VCEP v2.0 PVS1 rule, nonsense variants introducing PTC at or before codon 1341 qualify for PVS1 at Very Strong strength. Loss of function is an established disease mechanism for MSH6 in Lynch syndrome.
PM2Supporting
PM2 · supporting
Under MSH6 VCEP v2.0, PM2 at Supporting strength applies when the variant is absent or extremely rare in gnomAD v4 with an allele frequency below 0.00002 (<1 in 50,000 alleles). This variant has an allele frequency of 1.86e-06 in gnomAD v4.1 (3/1,613,890 alleles, 0 homozygotes), which is well below the threshold. It is also extremely rare in gnomAD v2.1 (1/251,182 alleles).
PP5Supporting
PP5 · supporting
Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
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: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PP5 supporting; maps to Pathogenic.
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
3 / 1,613,890 alleles
gnomAD v4.1: 3 / 1,613,890 alleles. Recorded AF 1.85886e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98118e-06; MAF= 0.00040%, 1/251182 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
22 reported laboratory submissions
22 Pathogenic. ClinVar API review status: reviewed by expert panel.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
5 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52273723, n = 5 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, with the data and sources behind each one.
29 criteria with recorded statuses: 3 met · 14 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000179.2:c.1483C>T (p.Arg495Ter) is a nonsense variant in MSH6 that introduces a premature termination codon at position 495, well below the VCEP cutoff of codon 1341, qualifying for PVS1 at Very Strong strength.
The variant is extremely rare in population databases with an allele frequency of 1.86e-06 in gnomAD v4.1 (3/1,613,890 alleles, 0 homozygotes), meeting the MSH6 VCEP PM2_Supporting threshold of <0.00002.
This variant has been reported in ClinVar (VariationID 89197) as Pathogenic by the InSiGHT expert panel (3-star review status) and by 22 clinical laboratories, supporting PP5 at Supporting strength.
The variant was identified in one Brazilian Lynch syndrome proband (PMID:26437257, patient ID-152) with colon cancer at age 59 meeting Bethesda guideline criteria; no MSI, IHC, or co-segregation data were available.
Applying the ClinGen InSiGHT MSH6 VCEP v2.0 combination rules: PVS1 (Very Strong) + PM2 (Supporting) + PP5 (Supporting) meets Rule 4 (1 Very Strong + ≥2 Supporting) for a classification of Pathogenic.
No criteria match.
Met · 3
PVS1 Very strongNM_000179.2:c.1483C>T is a nonsense variant that introduces a premature termination codon (p.Arg495Ter) at codon 495, which is well below the VCEP threshold of codon 1341 for MSH6. Under the ClinGen InSiGHT MSH6 VCEP v2.0 PVS1 rule, nonsense variants introducing PTC at or before codon 1341 qualify for PVS1 at Very Strong strength. Loss of function is an established disease mechanism for MSH6 in Lynch syndrome. Details ▾Hide ▴
Evidence considered
- Nonsense variant introducing PTC at codon 495
- well below the VCEP cutoff of codon 1341
- LoF is established disease mechanism for MSH6 in Lynch syndrome per CSPEC/VCEP
Sources
PM2 SupportingUnder MSH6 VCEP v2.0, PM2 at Supporting strength applies when the variant is absent or extremely rare in gnomAD v4 with an allele frequency below 0.00002 (<1 in 50,000 alleles). This variant has an allele frequency of 1.86e-06 in gnomAD v4.1 (3/1,613,890 alleles, 0 homozygotes), which is well below the threshold. It is also extremely rare in gnomAD v2.1 (1/251,182 alleles). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 1.86e-06 (3/1
- 613
- 890)
- well below VCEP PM2_Supporting threshold of 0.00002
- gnomAD v2.1 AF = 3.98e-06 (1/251
- 182)
Sources
PP5 SupportingExpert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 89197: Pathogenic
- reviewed by expert panel (InSiGHT
- 3-star)
- 22 clinical laboratories classify as Pathogenic
- ClinVar expert panel classification
Sources
Not met · 14 · evaluated, threshold not reached
PS1 PS1 requires a different nucleotide change encoding the same amino acid change (p.Arg495Ter) previously classified as Pathogenic by this VCEP. No evidence of an alternate nucleotide substitution creating the same stop codon (e.g., c.1483C>G or c.1484G>A) having been classified as Pathogenic by the InSiGHT VCEP was identified. Details ▾Hide ▴
Still missing
- No alternate nucleotide change creating p.Arg495Ter previously classified as Pathogenic by VCEP
Sources
PS2 PS2 requires de novo occurrence data with confirmed maternity/paternity. No de novo observations for NM_000179.2:c.1483C>T were identified in any reviewed literature or database. Details ▾Hide ▴
Still missing
- No de novo data available for this variant
PS3 PS3 requires variant-specific experimental functional data or systematic characterization of the variant position through calibrated functional assays as defined by the VCEP MMR functional assay documentation. Although c.1483C>T is a nonsense variant predicted to result in complete loss of function via NMD, no direct functional assay data for this exact variant was identified. The paper by Carneiro da Silva et al. (PMID:26437257) reports the variant in a Lynch syndrome patient but does not include functional studies. The predicted loss-of-function effect is already captured by PVS1. Details ▾Hide ▴
Evidence considered
- Nonsense variant predicted to cause NMD and complete loss of MSH6 protein
- but no direct experimental functional data available
Still missing
- No variant-specific functional assay data
- predicted null effect already accounted for by PVS1
Sources
vcep_functional_assay_svi_documentation_mmrPMID:26437257 ↗
PP1 PP1 requires co-segregation data with a Bayes Likelihood Ratio meeting VCEP thresholds. No pedigree or co-segregation data were available for this variant. The paper by Carneiro da Silva et al. (PMID:26437257) reports the variant in a single patient (ID-152, colon cancer at age 59, meeting Bethesda guideline) but provides no multi-generational co-segregation analysis. Details ▾Hide ▴
Evidence considered
- Single proband reported (ID-152
- CC age 59) without co-segregation data
Still missing
- No co-segregation or pedigree data available
Sources
PP3 PP3 under MSH6 VCEP v2.0 requires either: (a) a missense variant with HCI prior probability of pathogenicity >0.68, or (b) a predicted splice defect at a non-canonical splice site with SpliceAI delta score ≥0.2. This is a nonsense variant, not a missense substitution, so HCI prior lookup is not applicable (confirmed absent from the MSH6 HCI-PRIORS table). SpliceAI predicts no splicing impact (max delta score = 0.04). Neither PP3 pathway is satisfied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.04 (<0.2 threshold)
- Not a missense variant — HCI prior not applicable
Sources
PP4 PP4 under MSH6 VCEP v2.0 requires MSI-H colorectal or endometrial tumors and/or loss of MMR protein expression consistent with the variant location. The single reported proband (Carneiro da Silva et al., PMID:26437257, patient ID-152) had colon cancer at age 59 meeting Bethesda guideline, but no MSI or IHC data were reported for this patient. Without tumor phenotype data, PP4 cannot be applied. Details ▾Hide ▴
Evidence considered
- Single proband reported with CC at age 59 but no MSI/IHC data available
Still missing
- No tumor MSI or IHC data for this variant
Sources
BA1 BA1 under MSH6 VCEP v2.0 requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%) and exclusion as a founder pathogenic variant. This variant has an allele frequency of 1.86e-06 in gnomAD v4.1, far below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 1.86e-06
- far below BA1 threshold of 0.0022
Sources
BS1 BS1 under MSH6 VCEP v2.0 requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 and < 0.0022 (0.022%–0.22%). This variant has an allele frequency of 1.86e-06 in gnomAD v4.1, below the BS1 lower threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 1.86e-06
- below BS1 lower threshold of 0.00022
Sources
BS2 BS2 under MSH6 VCEP v2.0 requires co-occurrence in trans with a known pathogenic variant in a patient with colorectal cancer after age 45 without clinical manifestations of CMMRD. No such co-occurrence data were identified. Details ▾Hide ▴
BS3 BS3 under MSH6 VCEP v2.0 requires calibrated functional assays demonstrating functional odds for pathogenicity ≤ 0.05 (Strong) or between 0.05 and 0.48 (Supporting), or variant-specific proficient function in protein/mRNA-based assays. No benign functional data were identified for this variant. The variant is a nonsense mutation predicted to cause complete loss of function, which is inconsistent with a BS3 determination. Details ▾Hide ▴
Still missing
- No benign functional data
- nonsense variant predicted to be loss-of-function
Sources
vcep_functional_assay_svi_documentation_mmrcspec ↗
BS4 BS4 under MSH6 VCEP v2.0 requires lack of co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio meeting specified thresholds. No segregation data were available for this variant. Details ▾Hide ▴
BP5 BP5 under MSH6 VCEP v2.0 requires tumors with MSS and/or no loss of MMR protein expression inconsistent with the gene, or BRAF V600E/MLH1 methylation with MSI-H. No tumor phenotype data (MSI status or IHC) were reported for this variant. The single reported proband (PMID:26437257) had no MSI or IHC data available. Details ▾Hide ▴
BP6 BP6 applies when a reputable source classifies the variant as benign. ClinVar VariationID 89197 is classified as Pathogenic by the InSiGHT expert panel and 22 clinical laboratories — not benign. The BP6 override rule for ClinVar 3-star expert panels applies only when the classification direction is benign; here the classification is Pathogenic. Details ▾Hide ▴
PS5 PS5 is not defined by the MSH6 VCEP. The ClinVar entry (VariationID 89197) is classified as Pathogenic by the InSiGHT expert panel, which is the same body that authored this VCEP. Citing the VCEP's own expert panel classification as external reputable-source evidence would be circular. No independent external source distinct from the VCEP was identified. Details ▾Hide ▴
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 VCEPPS4 is marked Not Applicable by the MSH6 VCEP v2.0. Details ▾Hide ▴
Sources
PM1 VCEPPM1 is marked Not Applicable by the MSH6 VCEP v2.0. Details ▾Hide ▴
Sources
PM3 N/ABiallelic/recessive criterion; skipped per assessment instructions. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPIn-frame deletion/insertion criterion; not applicable to this substitution variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AThe variant is a nonsense change (p.Arg495Ter), not a missense substitution. PM5 under VCEP applies only to missense changes at amino acid residues where a different missense change was classified as Pathogenic or Likely Pathogenic. Additionally, the pm5_candidates module confirms no eligible same-residue missense comparators exist. Details ▾Hide ▴
Sources
pm5_candidatescspec ↗
PM6 VCEPPM6 is marked Not Applicable by the MSH6 VCEP v2.0. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is marked Not Applicable by the MSH6 VCEP v2.0. Details ▾Hide ▴
Sources
BP1 VCEPBP1 is marked Not Applicable by the MSH6 VCEP v2.0. Details ▾Hide ▴
Sources
BP2 VCEPBP2 is marked Not Applicable by the MSH6 VCEP v2.0. Details ▾Hide ▴
Sources
BP3 VCEPIn-frame deletion/insertion criterion; not applicable to this substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 under MSH6 VCEP v2.0 applies only to missense variants with HCI prior probability <0.11 or intronic/synonymous variants with SpliceAI delta score ≤0.1. This is a nonsense variant in exon 4; neither BP4 pathway is applicable. Details ▾Hide ▴
Evidence considered
- Nonsense variant — BP4 is defined only for missense (HCI prior) or intronic/synonymous (SpliceAI) variants
Sources
BP7 N/ABP7 under MSH6 VCEP v2.0 applies only to synonymous (silent) or intronic variants at or beyond positions -21/+7. This is a nonsense variant in exon 4, creating a premature termination codon. BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Nonsense variant — BP7 is defined only for synonymous or intronic variants
Sources
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.2
- Coding (HGVS c.)
- NM_000179.2:c.1483C>T
- Protein (HGVS p.)
- NP_000170.1:p.(Arg495Ter)
- GRCh38
- chr2:47799466 C>T
- GRCh37
- chr2:48026605 C>T
- ClinVar
- 89197
- COSMIC
- COSV52273723
Gene diagram
Every interpreted variant in MSH6, mapped onto the exon structure of NM_000179.2. Select a row to find it on the plot.
MSH6NM_000179.2
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
3 / 1,613,890 alleles
AF 1.86e-06 · 0 homozygotes
gnomAD v2.1
1 / 251,182 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,613,890 alleles · 0 hom
| Remaining individuals1 / 62,506 | 1.6e-05 |
| South Asian1 / 91,064 | 1.1e-05 |
| European (non-Finnish)1 / 1,179,992 | 8.5e-07 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,182 alleles · 0 hom
| South Asian1 / 30,616 | 3.3e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85886e-06; MAF= 0.00019%, 3/1613890 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59985e-05; MAF= 0.00160%, 1/62506 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98118e-06; MAF= 0.00040%, 1/251182 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.537
How the predictions were used
PP3 PP3 under MSH6 VCEP v2.0 requires either: (a) a missense variant with HCI prior probability of pathogenicity >0.68, or (b) a predicted splice defect at a non-canonical splice site with SpliceAI delta score ≥0.2. This is a nonsense variant, not a missense substitution, so HCI prior lookup is not applicable (confirmed absent from the MSH6 HCI-PRIORS table). SpliceAI predicts no splicing impact (max delta score = 0.04). Neither PP3 pathway is satisfied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.04 (<0.2 threshold)
- Not a missense variant — HCI prior not applicable
Sources
BP4 N/ABP4 under MSH6 VCEP v2.0 applies only to missense variants with HCI prior probability <0.11 or intronic/synonymous variants with SpliceAI delta score ≤0.1. This is a nonsense variant in exon 4; neither BP4 pathway is applicable. Details ▾Hide ▴
Evidence considered
- Nonsense variant — BP4 is defined only for missense (HCI prior) or intronic/synonymous (SpliceAI) variants
Sources
BP7 N/ABP7 under MSH6 VCEP v2.0 applies only to synonymous (silent) or intronic variants at or beyond positions -21/+7. This is a nonsense variant in exon 4, creating a premature termination codon. BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Nonsense variant — BP7 is defined only for synonymous or intronic variants
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.536677.
7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
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PMID 24362816 ↗Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.Thompson BA et al. · 2014Describes the InSiGHT 5-tiered classification scheme applied to 2,360 unique MMR gene variants. The exact variant NM_000179.2:c.1483C>T (p.Arg495Ter) was not identified in the full text of this paper. This publication underpins the classification framework rather than providing variant-specific evidence.Does not name this variant
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PMID 1651234 ↗Altering the conserved nucleotide binding motif in the Salmonella typhimurium MutS mismatch repair protein affects both its ATPase and mismatch binding activities.Biochemical study of the Salmonella typhimurium MutS protein, examining ATPase and mismatch binding activities of mutant MutS proteins with alterations in the conserved nucleotide binding motif. No human MSH6 variants were discussed.Does not name this variant
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PMID 22810696 ↗Comprehensive molecular characterization of human colon and rectal cancer.TCGA comprehensive molecular characterization of 276 human colon and rectal carcinomas, analyzing exome sequence, copy number, methylation, and expression. Focuses on somatic alterations in colorectal cancer. NM_000179.2:c.1483C>T was not identified in this paper.Does not name this variant
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PMID 24755471 ↗Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer.Profiling of 70 colorectal cancer cell lines for mutations and DNA copy number by whole-exome sequencing, comparing cell line models to primary tumor molecular subtypes. NM_000179.2:c.1483C>T was not identified in this paper.Does not name this variant
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PMID 9111312 ↗Genetic and biochemical analysis of Msh2p-Msh6p: role of ATP hydrolysis and Msh2p-Msh6p subunit interactions in mismatch base pair recognition.Genetic and biochemical analysis of Saccharomyces cerevisiae Msh2p-Msh6p complex, examining ATP hydrolysis and subunit interactions in mismatch base pair recognition. No human MSH6 variant data was reported.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 consensus guidelines for sequence variant interpretation. This is the foundational methodological reference for the ACMG/AMP classification framework. NM_000179.2:c.1483C>T is not discussed.Does not name this variant
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PMID 26437257 ↗Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome.Carneiro da Silva F et al. · 2015NM_000179.2:c.1483C>T (p.Arg495Ter) reported in a Brazilian Lynch syndrome cohort of 116 probands. Patient ID-152 carried this MSH6 nonsense variant with colon cancer diagnosed at age 59, meeting Bethesda guideline criteria. No IHC or MSI data were available for this patient. The variant was described as novel at the time of publication.Names this variant
Quoted passage
152 MSH6 - c.1483C>T p.Arg495* 04 CC (59) BG Current study—Novel
Table 1 (pathogenic mutations found in 116 LS patients), Results section 'Genetic analysis'
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,613,890 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
22 Pathogenic
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/89197/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48026605-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47799466-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47799466-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.2%3Ac.1483…
- OncoKB ↗www.oncokb.org/gene/MSH6/R495*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124984614
- 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= 1.85886e-06; MAF= 0.00019%, 3/1613890 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59985e-05; MAF= 0.00160%, 1/62506 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98118e-06; MAF= 0.00040%, 1/251182 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (22 clinical laboratories) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 89197)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.536677.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52273723, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.