About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.188C>T, p.(Ser63Phe)
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
NM_000179.2:c.188C>T is extremely rare in gnomAD v4.1 (1/1,509,420 alleles; AF = 6.625e-07), meeting the MSH6 VCEP PM2_Supporting threshold of allele frequency < 0.00002 (fewer than 1 in 50,000 alleles). The variant is absent from gnomAD v2.1 and absent from all populations except a single European (non-Finnish) allele.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
The HCI prior probability for p.Ser63Phe is 0.003, meeting the MSH6 VCEP BP4_Supporting threshold of < 0.11. Multiple in silico predictors are consistent with a benign effect: REVEL score is 0.195 (below typical pathogenic threshold), BayesDel score is -0.269 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta = 0.00).
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 benign; 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
1 / 1,509,420 alleles
gnomAD v4.1: 1 / 1,509,420 alleles. Recorded AF 6.62506e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in 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
2 reported laboratory submissions
2 Uncertain significance.
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
6 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52275784, n = 6 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.
26 criteria with recorded statuses: 2 met · 6 not met · 8 not assessed · 10 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.188C>T (p.Ser63Phe) is a missense variant in MSH6 exon 1. The variant is extremely rare, observed in 1 of 1,509,420 alleles (AF = 6.625e-07) in gnomAD v4.1 and absent from gnomAD v2.1, meeting PM2_Supporting under the InSiGHT MSH6 VCEP v2.0.0 framework.
Multiple in silico predictors are consistent with a benign effect. The HCI prior probability for p.Ser63Phe is 0.003, meeting BP4_Supporting (threshold < 0.11). REVEL score is 0.195, BayesDel score is -0.269, and SpliceAI predicts no splicing impact (max delta = 0.00).
PVS1 is not applicable (missense variant). PS1 is not met (no alternate nucleotide change encoding p.Ser63Phe classified as P/LP by this VCEP). PM5 is not met because PP3 is not supporting (HCI prior 0.003, far below PP3_Supporting threshold of >0.68). Multiple VCEP criteria are explicitly Not Applicable: PS4, PP5, PM1, PM6, PP2, BP1, BP2, BP6.
The variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (VariationID: 1053294). It has been observed in somatic cancers (COSMIC COSV52275784, n = 6). No variant-specific functional data, segregation data, de novo occurrences, or tumor phenotype data were identified.
At present, the only scored criteria are PM2_Supporting (pathogenic) and BP4_Supporting (benign), which offset. Multiple criteria remain unassessed due to absence of clinical, functional, and segregation data. Comprehensive assessment awaits functional assay results for p.Ser63Phe, tumor MSI/IHC data from variant carriers, and segregation analysis.
No criteria match.
Met · 2
PM2 SupportingNM_000179.2:c.188C>T is extremely rare in gnomAD v4.1 (1/1,509,420 alleles; AF = 6.625e-07), meeting the MSH6 VCEP PM2_Supporting threshold of allele frequency < 0.00002 (fewer than 1 in 50,000 alleles). The variant is absent from gnomAD v2.1 and absent from all populations except a single European (non-Finnish) allele. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1/1
- 509
- 420 total alleles (AF = 6.625e-07)
- 0 homozygotes. gnomAD v2.1: absent. VCEP PM2_Supporting threshold: AF < 0.00002.
Sources
BP4 SupportingThe HCI prior probability for p.Ser63Phe is 0.003, meeting the MSH6 VCEP BP4_Supporting threshold of < 0.11. Multiple in silico predictors are consistent with a benign effect: REVEL score is 0.195 (below typical pathogenic threshold), BayesDel score is -0.269 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
- HCI prior = 0.003 (threshold BP4_Supporting: < 0.11
- met). REVEL = 0.195. BayesDel = -0.269. SpliceAI max delta = 0.00. Multiple in silico tools converge on a benign prediction.
Sources
Not met · 6 · evaluated, threshold not reached
PS1 No alternative nucleotide change encoding p.Ser63Phe has been classified by the InSiGHT Hereditary Colorectal Cancer/Polyposis EP as Pathogenic or Likely Pathogenic. The only nucleotide substitution producing p.Ser63Phe is c.188C>T itself. The VCEP pilot variants spreadsheet contains no entries at codon 63 of MSH6. Details ▾Hide ▴
Evidence considered
- VCEP PS1 rules require an alternate nucleotide change at the same amino acid already classified as P/LP
- no such comparator exists for p.Ser63Phe. The VCEP pilot variants spreadsheet (VCEP-pilot-variants---MMR.xlsx) was searched for MSH6 codon 63 entries and none were found.
Sources
cspec ↗hci_prior
PM5 The MSH6 VCEP PM5 rule requires PP3 to be supporting for the missense change as a prerequisite. PP3 is not met for p.Ser63Phe (HCI prior probability = 0.003, far below the 0.68 threshold for PP3_Supporting). Therefore PM5 cannot be applied regardless of whether a same-residue comparator exists. Details ▾Hide ▴
Evidence considered
- HCI prior probability for p.Ser63Phe = 0.003
- which does not meet PP3 thresholds (>0.68 for Supporting
- >0.81 for Moderate). VCEP PM5 rule: 'Only use PM5 if PP3 is supporting for the missense change.'
Sources
cspec ↗hci_prior
PP3 The HCI prior probability for p.Ser63Phe is 0.003, which falls far below the MSH6 VCEP PP3_Supporting threshold of >0.68. REVEL score is 0.195 and BayesDel score is -0.269, both consistent with a benign in silico prediction. SpliceAI predicts no splicing impact (max delta = 0.00). Multiple in silico tools collectively do not support a pathogenic classification. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.003 (thresholds: PP3_Moderate >0.81
- PP3_Supporting >0.68
- both unmet). REVEL = 0.195 (low). BayesDel = -0.269 (negative
- favors benign). SpliceAI max delta = 0.00 (no splice impact).
Sources
BA1 The MSH6 VCEP BA1 threshold requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%). The variant has an allele frequency of 6.625e-07 (0.000066%) in gnomAD v4.1, far below this threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF = 6.625e-07
- grpmax_faf = null. VCEP BA1 threshold: ≥ 0.0022. Not met.
Sources
BS1 The MSH6 VCEP BS1 threshold requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 (0.022%). The variant has an allele frequency of 6.625e-07 (0.000066%) in gnomAD v4.1, well below this threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF = 6.625e-07. VCEP BS1 threshold: ≥ 0.00022. Not met.
Sources
BP7 NM_000179.2:c.188C>T is a missense variant (p.Ser63Phe), not a synonymous (silent) or intronic variant at or beyond -21/+7. BP7 applies only to synonymous and intronic variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- does not meet the BP7 definition (synonymous or intronic variant at or beyond -21/+7).
Sources
Not assessed · 8 · no assessment recorded
PS2 No de novo occurrence with confirmed parentage has been identified for NM_000179.2:c.188C>T in the available literature, ClinVar submissions, or databases. The exploratory literature search found no de novo reports. Details ▾Hide ▴
Evidence considered
- Exploratory search for de novo evidence returned no findings. ClinVar submissions do not include de novo assertions.
Still missing
- No de novo data identified. Systematic review of clinical testing laboratory records and family studies may reveal unreported de novo occurrences.
PS3 No calibrated functional assay data for p.Ser63Phe was identified in the VCEP functional assay documentation spreadsheet or in available literature. Kariola et al. 2014 (PMID:24362816) performed a functional complementation assay for 74 MSH6 missense variants but the full text is not available to confirm whether p.Ser63Phe was among those tested or what the result was. OncoKB reports no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- Exploratory search identified PMID:24362816 (Kariola et al. 2014) as potentially containing functional data but full text unavailable for verification. VCEP Functional-assay-SVI-documentation-MMR.xlsx does not list c.188C>T. OncoKB classification: Unknown Oncogenic Effect.
Still missing
- PMID:24362816 full text needed to determine if p.Ser63Phe was among 74 tested variants and functional outcome. Calibrated functional odds for pathogenicity unavailable.
Sources
PP1 No co-segregation data with disease in pedigrees has been identified for NM_000179.2:c.188C>T. The variant is extremely rare, and no published multiplex families demonstrating variant-disease tracking were found. Details ▾Hide ▴
Evidence considered
- Exploratory search for co-segregation data returned no findings.
Still missing
- No co-segregation data available. Family studies and segregation analysis would be needed to assess this criterion.
PP4 No tumor MSI/IHC data for patients harboring NM_000179.2:c.188C>T was identified in the available evidence. The criterion requires CRC/Endometrial MSI-H tumors and/or loss of MMR protein expression consistent with the variant location. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available.
Still missing
- No MSI/IHC data from tumors of variant carriers identified.
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 has been identified. Details ▾Hide ▴
Evidence considered
- No biallelic observation data available.
Still missing
- No trans co-occurrence data with pathogenic MSH6 variants identified.
BS3 No calibrated functional assay data demonstrating proficient MMR function for p.Ser63Phe is available. The VCEP functional assay documentation spreadsheet does not list this variant. Kariola et al. 2014 (PMID:24362816) may contain relevant data but full text is unavailable for verification. Details ▾Hide ▴
Evidence considered
- Exploratory search identified potential functional data in PMID:24362816 but cannot be verified without full text. VCEP Functional-assay-SVI-documentation-MMR.xlsx does not include c.188C>T.
Still missing
- PMID:24362816 full text needed. No calibrated functional odds for pathogenicity ≤ 0.05 available.
BS4 No lack-of-segregation data (variant present in unaffected family members) has been identified for NM_000179.2:c.188C>T. Details ▾Hide ▴
Evidence considered
- Exploratory search for lack-of-segregation data returned no findings.
Still missing
- No segregation data available to assess non-segregation with disease.
BP5 No tumor data (CRC/Endometrial MSS status, MMR protein expression, BRAF V600E, or MLH1 methylation) is available for patients harboring NM_000179.2:c.188C>T. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available to assess BP5.
Still missing
- No tumor MSS/IHC/BRAF/methylation data from variant carriers identified.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000179.2:c.188C>T is a missense substitution (p.Ser63Phe), not a null variant (nonsense, frameshift, canonical splice, or initiation codon). PVS1 is not applicable to missense variants under either the MSH6 VCEP framework or generic ACMG/AMP guidelines. Details ▾Hide ▴
Evidence considered
- Missense variant
- does not qualify for any PVS1 strength category in the MSH6 VCEP decision tree (nonsense/frameshift PTC ≤ codon 1341
- canonical splice
- initiation codon).
Sources
pvs1_variant_assessmentcspec ↗
PS4 VCEPThe ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis EP Specifications for MSH6 Version 2.0.0 explicitly marks PS4 as Not Applicable for this VCEP. Details ▾Hide ▴
PM1 VCEPThe ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis EP Specifications for MSH6 Version 2.0.0 explicitly marks PM1 as Not Applicable for this VCEP. Details ▾Hide ▴
PM6 VCEPThe ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis EP Specifications for MSH6 Version 2.0.0 explicitly marks PM6 as Not Applicable for this VCEP. Details ▾Hide ▴
PP2 VCEPThe ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis EP Specifications for MSH6 Version 2.0.0 explicitly marks PP2 as Not Applicable for this VCEP. Details ▾Hide ▴
PP5 VCEPThe ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis EP Specifications for MSH6 Version 2.0.0 explicitly marks PP5 as Not Applicable for this VCEP. Details ▾Hide ▴
BP1 VCEPThe ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis EP Specifications for MSH6 Version 2.0.0 explicitly marks BP1 as Not Applicable for this VCEP. Details ▾Hide ▴
BP2 VCEPThe ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis EP Specifications for MSH6 Version 2.0.0 explicitly marks BP2 as Not Applicable for this VCEP. Details ▾Hide ▴
BP6 VCEPThe ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis EP Specifications for MSH6 Version 2.0.0 explicitly marks BP6 as Not Applicable, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
PS5 N/AThe ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis EP Specifications for MSH6 Version 2.0.0 explicitly marks PP5 as Not Applicable for this VCEP. Details ▾Hide ▴
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.2
- Coding (HGVS c.)
- NM_000179.2:c.188C>T
- Protein (HGVS p.)
- NP_000170.1:p.(Ser63Phe)
- GRCh38
- chr2:47783421 C>T
- GRCh37
- chr2:48010560 C>T
- ClinVar
- 1053294
- COSMIC
- COSV52275784
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
1 / 1,509,420 alleles
AF 6.63e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.6e-07 · 1 / 1,509,420 alleles · 0 hom
| European (non-Finnish)1 / 1,131,018 | 8.8e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.62506e-07; MAF= 0.00007%, 1/1509420 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.84159e-07; MAF= 0.00009%, 1/1131018 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.195
- BayesDel
- -0.269
How the predictions were used
BP4 SupportingThe HCI prior probability for p.Ser63Phe is 0.003, meeting the MSH6 VCEP BP4_Supporting threshold of < 0.11. Multiple in silico predictors are consistent with a benign effect: REVEL score is 0.195 (below typical pathogenic threshold), BayesDel score is -0.269 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
- HCI prior = 0.003 (threshold BP4_Supporting: < 0.11
- met). REVEL = 0.195. BayesDel = -0.269. SpliceAI max delta = 0.00. Multiple in silico tools converge on a benign prediction.
Sources
PP3 The HCI prior probability for p.Ser63Phe is 0.003, which falls far below the MSH6 VCEP PP3_Supporting threshold of >0.68. REVEL score is 0.195 and BayesDel score is -0.269, both consistent with a benign in silico prediction. SpliceAI predicts no splicing impact (max delta = 0.00). Multiple in silico tools collectively do not support a pathogenic classification. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.003 (thresholds: PP3_Moderate >0.81
- PP3_Supporting >0.68
- both unmet). REVEL = 0.195 (low). BayesDel = -0.269 (negative
- favors benign). SpliceAI max delta = 0.00 (no splice impact).
Sources
BP7 NM_000179.2:c.188C>T is a missense variant (p.Ser63Phe), not a synonymous (silent) or intronic variant at or beyond -21/+7. BP7 applies only to synonymous and intronic variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- does not meet the BP7 definition (synonymous or intronic variant at or beyond -21/+7).
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.195. BayesDel score = -0.269383. HCI prior probability for pathogenicity = 0.003. Custom PP2 score = 0.027.
2 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 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,509,420 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
2 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/1053294/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48010560-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47783421-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47783421-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.2%3Ac.188C…
- OncoKB ↗www.oncokb.org/gene/MSH6/S63F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124983043
- 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= 6.62506e-07; MAF= 0.00007%, 1/1509420 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.84159e-07; MAF= 0.00009%, 1/1131018 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1053294)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.195. BayesDel score = -0.269383. HCI prior probability for pathogenicity = 0.003. Custom PP2 score = 0.027.
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; COSV52275784, n = 6 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.