About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.3412G>A, p.(Gly1138Arg)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v4.1 (0 alleles across 1,614,568 total alleles) and gnomAD v2.1. This meets the VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles).
PP3Moderate
PP3 · moderate
The HCI prior probability of pathogenicity for c.3412G>A (p.G1138R) is 0.9617, which exceeds the VCEP PP3_Moderate threshold of >0.81. REVEL score is 0.947, consistent with a deleterious prediction.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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: PM2 supporting, PP3 moderate; 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. 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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MSH6 VCEP v2.0.0, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 13 not met · 0 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
PM2_Supporting is met: the variant is absent from gnomAD v4.1 (0/1,614,568 alleles) and gnomAD v2.1, meeting the VCEP threshold of allele frequency <0.00002.
PP3_Moderate is met: the HCI prior probability of pathogenicity for c.3412G>A (p.G1138R) is 0.9617, exceeding the VCEP PP3_Moderate threshold of >0.81. REVEL score is 0.947, consistent with a deleterious prediction.
PVS1 is not applicable: this is a missense variant (p.Gly1138Arg), not a null variant, and SpliceAI predicts no splice impact (max delta = 0.01).
PS3 is not met: no calibrated functional assay data exists for p.Gly1138Arg in the VCEP functional assay documentation or published literature.
PS1, PS2, PM5, PP1, PP4, BA1, BS1, BS2, BS3, BS4, BP4, BP5 are not met due to absence of supporting evidence.
PS4, PS5, PM1, PM6, PP2, PP5, BP1, BP2, BP3, BP6, BP7, PM3, PM4 are not applicable per the InSiGHT MMR VCEP v2.0.0 specifications or because the variant class does not meet the criterion definition.
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from gnomAD v4.1 (0 alleles across 1,614,568 total alleles) and gnomAD v2.1. This meets the VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (0/1
- 614
- 568 alleles
- AF=0.0)
- absent from gnomAD v2.1
- absent from gnomAD-Canada v1.0.
Sources
PP3 ModerateThe HCI prior probability of pathogenicity for c.3412G>A (p.G1138R) is 0.9617, which exceeds the VCEP PP3_Moderate threshold of >0.81. REVEL score is 0.947, consistent with a deleterious prediction. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.9617 (>0.81 threshold for PP3_Moderate)
- REVEL = 0.947
- BayesDel = 0.451.
Sources
Not met · 13 · evaluated, threshold not reached
PS1 No different nucleotide change encoding the same amino acid (p.Gly1138Arg) has been established as Pathogenic by the InSiGHT MMR VCEP. No alternate nucleotide substitution at codon 1138 was identified in ClinVar or the VCEP pilot variant spreadsheet. Details ▾Hide ▴
PS2 No de novo occurrence has been reported for this variant. De novo events in Lynch syndrome genes are rare; no evidence was identified in ClinVar, literature, or exploratory search. Details ▾Hide ▴
Evidence considered
- ClinVar submissions contain no de novo annotation
- exploratory literature search yielded no de novo reports.
Still missing
- No de novo testing data available.
Sources
PS3 No calibrated functional assay data exists for p.Gly1138Arg. The VCEP functional assay SVI documentation spreadsheet (Drost 2018/2020, Jia/Scott 2021/2022, Rath 2022, Thompson 2013, Morak 2019, Bouvet 2019 datasets) does not include this variant. No variant-specific functional evidence was identified in the literature. Details ▾Hide ▴
Evidence considered
- VCEP MMR functional assay spreadsheet searched
- p.Gly1138Arg not included in any calibrated functional dataset. No variant-specific functional study found in literature.
Still missing
- No functional data available for this variant.
Sources
vcep_functional_assay_svi_documentation_mmr
PM5 No alternate missense change at codon 1138 has been classified as Pathogenic or Likely Pathogenic by the InSiGHT MMR VCEP. PM5 additionally requires PP3 to be met for the variant under assessment; PP3 is met at moderate strength, but the prerequisite comparator is absent. Details ▾Hide ▴
PP1 No co-segregation data with a combined Bayes Likelihood Ratio has been reported for this variant. No family studies with segregation analysis were identified. Details ▾Hide ▴
Evidence considered
- ClinVar submissions do not include segregation data
- exploratory literature search found no cosegregation studies.
Still missing
- No co-segregation or family study data available.
Sources
PP4 No MSI-H tumor data or MMR protein expression data (IHC) specific to this variant has been reported. PP4 requires CRC/endometrial MSI-H tumors and/or loss of MMR protein expression consistent with MSH6. Details ▾Hide ▴
Evidence considered
- No tumor MSI or IHC data for this variant found in ClinVar or literature.
Still missing
- No tumor phenotype data available.
Sources
BA1 The variant is absent from gnomAD v4.1 (0 alleles). The VCEP BA1_StandAlone threshold requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%). An absent variant does not meet this threshold. Details ▾Hide ▴
BS1 The variant is absent from gnomAD v4.1. The VCEP BS1_Strong threshold requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 and < 0.0022. An absent variant does not meet this threshold. Details ▾Hide ▴
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 reported. Confirmation of phase requires testing of parents or offspring, which has not been performed. Details ▾Hide ▴
Evidence considered
- No trans co-occurrence data reported in ClinVar or literature.
Still missing
- No trans phase data available.
Sources
BS3 No calibrated functional assay data showing a benign effect (functional odds for pathogenicity ≤ 0.05 for Strong or ≤ 0.48 for Supporting) exists for p.Gly1138Arg. The VCEP functional assay dataset does not include this variant. Details ▾Hide ▴
Evidence considered
- VCEP functional assay spreadsheet searched
- p.Gly1138Arg not included. No variant-specific functional data showing benign effect.
Still missing
- No functional data available.
Sources
vcep_functional_assay_svi_documentation_mmrcspec ↗
BS4 No lack-of-segregation data with a combined Bayes Likelihood Ratio has been reported for this variant. No family studies demonstrating absence of co-segregation with disease were identified. Details ▾Hide ▴
Evidence considered
- No segregation or lack-of-segregation data found in ClinVar or literature.
Still missing
- No family segregation data available.
Sources
BP4 The HCI prior probability of pathogenicity for c.3412G>A is 0.9617, which is far above the VCEP BP4_Supporting threshold of <0.11. The missense-specific BP4 rule does not apply. SpliceAI predicts no splicing impact (max delta = 0.01), but the BP4 rule for synonymous/intronic variants is not applicable to this missense variant. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.9617 (>0.11 BP4 cutoff)
- SpliceAI max delta = 0.01
- REVEL = 0.947.
Sources
BP5 No tumor data demonstrating MSS status or BRAF V600E/MLH1 methylation has been reported for patients carrying this variant. BP5 requires CRC/endometrial tumors with MSS and/or no loss of MMR protein expression, or alternative molecular etiology. Details ▾Hide ▴
Evidence considered
- No tumor MSS/MMR IHC/BRAF/methylation data for this variant reported in ClinVar or literature.
Still missing
- No tumor phenotype data available.
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Gly1138Arg). PVS1 per the MSH6 VCEP v2.0.0 applies only to null variants (nonsense/frameshift introducing PTC ≤ codon 1341, canonical splice variants, or confirmed splicing aberrations). SpliceAI predicts no splice impact (max delta = 0.01). Details ▾Hide ▴
Evidence considered
- Missense substitution c.3412G>A (p.Gly1138Arg) in exon 5
- SpliceAI max delta 0.01 confirms no cryptic splice effect.
Sources
PS4 VCEPPS4 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6. Details ▾Hide ▴
PM1 VCEPPM1 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6. Details ▾Hide ▴
PM3 N/APM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. Lynch syndrome is autosomal dominant and PM3 is not applicable in this context. Details ▾Hide ▴
Evidence considered
- Lynch syndrome is inherited in an autosomal dominant manner
- PM3 is a recessive-disorder criterion.
PM4 VCEPPM4 applies to non-repeat region in-frame deletions/insertions or stop-loss variants. This is a single-nucleotide missense substitution. Details ▾Hide ▴
Evidence considered
- Variant is a substitution (c.3412G>A)
- not an in-frame indel or stop-loss.
PM6 VCEPPM6 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6. Details ▾Hide ▴
PP2 VCEPPP2 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6. Details ▾Hide ▴
PP5 VCEPPP5 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP1 VCEPBP1 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6. Details ▾Hide ▴
BP2 VCEPBP2 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6. Details ▾Hide ▴
BP3 VCEPBP3 applies to in-frame indels in repetitive regions; this is a single-nucleotide missense substitution. Details ▾Hide ▴
Evidence considered
- Variant is a substitution (c.3412G>A)
- not an in-frame indel.
BP6 VCEPBP6 is designated Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7. This is a missense variant (c.3412G>A, p.Gly1138Arg) and does not qualify. Details ▾Hide ▴
PS5 N/APS5 is not defined in the InSiGHT MMR VCEP v2.0.0 framework for MSH6. Details ▾Hide ▴
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.2
- Coding (HGVS c.)
- NM_000179.2:c.3412G>A
- Protein (HGVS p.)
- NP_000170.1:p.(Gly1138Arg)
- GRCh38
- chr2:47803659 G>A
- GRCh37
- chr2:48030798 G>A
- ClinVar
- 2096360, 1959817, 650516
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.947
- BayesDel
- 0.451
How the predictions were used
PP3 ModerateThe HCI prior probability of pathogenicity for c.3412G>A (p.G1138R) is 0.9617, which exceeds the VCEP PP3_Moderate threshold of >0.81. REVEL score is 0.947, consistent with a deleterious prediction. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.9617 (>0.81 threshold for PP3_Moderate)
- REVEL = 0.947
- BayesDel = 0.451.
Sources
BP4 The HCI prior probability of pathogenicity for c.3412G>A is 0.9617, which is far above the VCEP BP4_Supporting threshold of <0.11. The missense-specific BP4 rule does not apply. SpliceAI predicts no splicing impact (max delta = 0.01), but the BP4 rule for synonymous/intronic variants is not applicable to this missense variant. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.9617 (>0.11 BP4 cutoff)
- SpliceAI max delta = 0.01
- REVEL = 0.947.
Sources
BP7 N/ABP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7. This is a missense variant (c.3412G>A, p.Gly1138Arg) and does not qualify. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.947. BayesDel score = 0.451433. HCI prior probability for pathogenicity = 0.9617. MAPP score = 36.52. Custom PP2 score = 0.999.
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
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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 outlining referral indications for cancer predisposition assessment. The document provides general personal and family history criteria for hereditary cancer syndromes but does not reference MSH6 c.3412G>A (p.Gly1138Arg) or any individual variant.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Nykamp et al. (2017) Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a methodological framework paper; it does not evaluate or mention MSH6 c.3412G>A (p.Gly1138Arg).Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
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/650516/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48030798-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47803659-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47803659-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.2%3Ac.3412…
- OncoKB ↗www.oncokb.org/gene/MSH6/G1138R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.3412G%3EA
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 650516)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.947. BayesDel score = 0.451433. HCI prior probability for pathogenicity = 0.9617. MAPP score = 36.52. Custom PP2 score = 0.999.
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.