About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.643G>C, p.(Val215Leu)
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_000179.3:c.643G>C is extremely rare in population databases. In gnomAD v4.1, the allele frequency is 1.24e-06 (2/1,610,788 alleles, no homozygotes), which is below the VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple computational predictors support a benign effect. The MSH6-specific HCI prior probability for pathogenicity is 0.0008, which falls below the VCEP BP4_Supporting threshold of <0.11. SpliceAI predicts no splicing impact (max delta score = 0.09, ≤0.1). REVEL score is 0.139 and BayesDel score is -0.503783, both consistent with a benign prediction.
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
2 / 1,610,788 alleles
gnomAD v4.1: 2 / 1,610,788 alleles. Recorded AF 1.24163e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.05108e-06; MAF= 0.00041%, 1/246848 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.87737e-06; MAF= 0.00089%, 1/112646 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.090 maximum delta
Recorded SpliceAI maximum delta score: 0.090. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
3 Uncertain significance · 1 Uncertain Significance · 1 Likely benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH6, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
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.
26 criteria with recorded statuses: 2 met · 13 not met · 1 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_000179.3:c.643G>C (p.Val215Leu) is a missense variant in exon 4 of MSH6. It is extremely rare in population databases (gnomAD v4.1 AF=1.24e-06), meeting PM2_Supporting per the InSiGHT MSH6 VCEP v2.0.0 threshold of <0.00002.
Multiple in silico predictors support a benign effect: the MSH6-specific HCI prior probability for pathogenicity is 0.0008, meeting BP4_Supporting (threshold <0.11). REVEL (0.139) and BayesDel (-0.503783) are also consistent with a benign prediction. SpliceAI predicts no splicing impact (max delta 0.09).
No variant-specific functional data, segregation data, tumor phenotype data, or de novo observations are available for this variant. The variant has not been classified by the VCEP pilot program and no comparator missense changes at codon 215 have been established as pathogenic.
This variant has been reported in ClinVar as Uncertain Significance by multiple clinical laboratories (ClinVar ID: 628619). Nine publications were reviewed; none mention NM_000179.3:c.643G>C.
No criteria match.
Met · 2
PM2 SupportingNM_000179.3:c.643G>C is extremely rare in population databases. In gnomAD v4.1, the allele frequency is 1.24e-06 (2/1,610,788 alleles, no homozygotes), which is below the VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles). Details ▾Hide ▴
BP4 SupportingMultiple computational predictors support a benign effect. The MSH6-specific HCI prior probability for pathogenicity is 0.0008, which falls below the VCEP BP4_Supporting threshold of <0.11. SpliceAI predicts no splicing impact (max delta score = 0.09, ≤0.1). REVEL score is 0.139 and BayesDel score is -0.503783, both consistent with a benign prediction. Details ▾Hide ▴
Evidence considered
- HCI prior=0.0008 (<0.11)
- SpliceAI delta=0.09 (≤0.1)
- REVEL=0.139
- BayesDel=-0.503783.
Sources
Not met · 13 · evaluated, threshold not reached
PS1 No nucleotide change encoding p.Val215Leu has been previously classified as Pathogenic or Likely Pathogenic by this VCEP. The VCEP pilot variants spreadsheet does not list any p.Val215 variant. Details ▾Hide ▴
Evidence considered
- VCEP pilot variants spreadsheet reviewed
- no p.Val215 or c.643 variant classified as P/LP.
Sources
vcep_vcep_pilot_variants_mmr
PS2 No de novo observations are reported in ClinVar or the literature for NM_000179.3:c.643G>C. De novo scoring per VCEP PS2 point system cannot be applied. Details ▾Hide ▴
Evidence considered
- ClinVar submissions contain no de novo assertions for this variant.
Still missing
- No de novo testing data available.
Sources
PS3 No variant-specific functional assay data for NM_000179.3:c.643G>C were identified in the VCEP functional assay documentation or in the reviewed literature. The HCI prior probability for pathogenicity is 0.0008, well below any calibrated functional odds threshold for PS3. Details ▾Hide ▴
Evidence considered
- HCI prior probability 0.0008
- variant absent from VCEP functional assay spreadsheet.
Still missing
- No variant-specific functional studies available.
Sources
vcep_functional_assay_svi_documentation_mmrhci_prior
PM5 No different missense change at codon 215 (Val215) has been classified as Pathogenic or Likely Pathogenic by this VCEP. PM5 candidate search returned no eligible comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate collection found zero P/LP comparators at residue 215
- VCEP pilot variants contain no p.Val215 entries.
Sources
pm5_candidatesvcep_vcep_pilot_variants_mmr
PP1 No co-segregation data are available for NM_000179.3:c.643G>C. No pedigrees with Bayes likelihood ratios are reported in ClinVar or the reviewed literature. Details ▾Hide ▴
Evidence considered
- No segregation data in ClinVar submissions or literature.
Still missing
- No family segregation studies available.
Sources
PP3 Multiple in silico predictors indicate a benign effect. The MSH6-specific HCI prior probability for pathogenicity is 0.0008, well below the VCEP PP3_Supporting threshold of >0.68. REVEL score is 0.139 and BayesDel score is -0.503783, both inconsistent with a damaging prediction. SpliceAI delta score is 0.09, indicating no splicing impact. Details ▾Hide ▴
Evidence considered
- HCI prior=0.0008 (<0.68)
- REVEL=0.139
- BayesDel=-0.503783
- SpliceAI max delta=0.09.
Sources
PP4 No MSI-H tumor data with MMR protein expression loss consistent with an MSH6 defect are reported for this variant. The VCEP PP4 threshold of ≥1 CRC/endometrial MSI-H tumor is not met. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available in ClinVar or literature.
Still missing
- No tumor MSI/IHC data available.
Sources
BA1 The gnomAD v4.1 allele frequency of 1.24e-06 (0.000124%) is far below the VCEP BA1 Stand-Alone threshold of ≥0.0022 (0.22%). Details ▾Hide ▴
BS1 The gnomAD v4.1 allele frequency of 1.24e-06 (0.000124%) is below the VCEP BS1 Strong threshold of ≥0.00022 (0.022%). Details ▾Hide ▴
BS2 No observation of this variant in trans with a known pathogenic MSH6 variant in a patient with CRC after age 45 without CMMRD features has been reported. Details ▾Hide ▴
Evidence considered
- No trans co-occurrence data available.
Still missing
- No phased genotype data available.
Sources
BS3 No variant-specific functional assay data demonstrating benign or normal function for NM_000179.3:c.643G>C are available. The variant is absent from the VCEP functional assay documentation spreadsheet. Details ▾Hide ▴
Evidence considered
- Variant not listed in VCEP functional assay spreadsheet
- HCI prior 0.0008 does not meet calibrated odds thresholds for BS3.
Still missing
- No functional studies demonstrating normal protein function.
Sources
vcep_functional_assay_svi_documentation_mmrhci_prior
BS4 No co-segregation data are available to assess lack of segregation with disease for NM_000179.3:c.643G>C. Details ▾Hide ▴
Evidence considered
- No segregation or non-segregation data available.
Still missing
- No family studies to evaluate co-segregation.
Sources
BP5 No tumor data demonstrating MSS status or inconsistent MMR protein expression are available for this variant. The VCEP BP5 thresholds for MSS tumors are not met. Details ▾Hide ▴
Evidence considered
- No tumor MSS/IHC data available.
Still missing
- No tumor phenotype data available.
Sources
Not assessed · 1 · no assessment recorded
PS5 PS5 is not defined in the InSiGHT MSH6 VCEP v2.0.0 criteria set and is not addressed by any local custom gene framework. No assessment can be performed. Details ▾Hide ▴
Evidence considered
- PS5 absent from VCEP criteria specification.
Still missing
- No framework rule for PS5 exists for MSH6.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_000179.3:c.643G>C is a missense variant (p.Val215Leu) and does not fall into any VCEP PVS1 null-variant bucket (nonsense, frameshift, canonical splice, large genomic alteration, or mRNA-confirmed splicing aberration). Details ▾Hide ▴
Evidence considered
- Missense substitution in exon 4 of MSH6
- no premature termination codon
- no splice consensus disruption.
Sources
pvs1_gene_contextpvs1_variant_assessment
PS4 VCEPPS4 is designated Not Applicable by the InSiGHT MSH6 VCEP v2.0.0. Details ▾Hide ▴
PM1 VCEPPM1 is designated Not Applicable by the InSiGHT MSH6 VCEP v2.0.0. Details ▾Hide ▴
PM6 VCEPPM6 is designated Not Applicable by the InSiGHT MSH6 VCEP v2.0.0. Details ▾Hide ▴
PP2 VCEPPP2 is designated Not Applicable by the InSiGHT MSH6 VCEP v2.0.0. Details ▾Hide ▴
PP5 VCEPPP5 is designated Not Applicable by the InSiGHT MSH6 VCEP v2.0.0. Details ▾Hide ▴
BP1 VCEPBP1 is designated Not Applicable by the InSiGHT MSH6 VCEP v2.0.0. Details ▾Hide ▴
BP2 VCEPBP2 is designated Not Applicable by the InSiGHT MSH6 VCEP v2.0.0. Details ▾Hide ▴
BP6 VCEPBP6 is designated Not Applicable by the InSiGHT MSH6 VCEP v2.0.0 as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7. NM_000179.3:c.643G>C is a missense variant (p.Val215Leu) and does not meet the VCEP BP7 criteria. Details ▾Hide ▴
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.643G>C
- Protein (HGVS p.)
- NP_000170.1:p.(Val215Leu)
- GRCh38
- chr2:47798626 G>C
- GRCh37
- chr2:48025765 G>C
- ClinVar
- 3633921, 2764954, 628619, 410407
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
2 / 1,610,788 alleles
AF 1.24e-06 · 0 homozygotes
gnomAD v2.1
1 / 246,848 alleles
AF 4.05e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,610,788 alleles · 0 hom
| East Asian1 / 44,898 | 2.2e-05 |
| European (non-Finnish)1 / 1,179,946 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4.1e-06 · 1 / 246,848 alleles · 0 hom
| European (non-Finnish)1 / 112,646 | 8.9e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.24163e-06; MAF= 0.00012%, 2/1610788 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22727e-05; MAF= 0.00223%, 1/44898 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.05108e-06; MAF= 0.00041%, 1/246848 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.87737e-06; MAF= 0.00089%, 1/112646 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.139
- BayesDel
- -0.504
How the predictions were used
BP4 SupportingMultiple computational predictors support a benign effect. The MSH6-specific HCI prior probability for pathogenicity is 0.0008, which falls below the VCEP BP4_Supporting threshold of <0.11. SpliceAI predicts no splicing impact (max delta score = 0.09, ≤0.1). REVEL score is 0.139 and BayesDel score is -0.503783, both consistent with a benign prediction. Details ▾Hide ▴
Evidence considered
- HCI prior=0.0008 (<0.11)
- SpliceAI delta=0.09 (≤0.1)
- REVEL=0.139
- BayesDel=-0.503783.
Sources
PP3 Multiple in silico predictors indicate a benign effect. The MSH6-specific HCI prior probability for pathogenicity is 0.0008, well below the VCEP PP3_Supporting threshold of >0.68. REVEL score is 0.139 and BayesDel score is -0.503783, both inconsistent with a damaging prediction. SpliceAI delta score is 0.09, indicating no splicing impact. Details ▾Hide ▴
Evidence considered
- HCI prior=0.0008 (<0.68)
- REVEL=0.139
- BayesDel=-0.503783
- SpliceAI max delta=0.09.
Sources
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7. NM_000179.3:c.643G>C is a missense variant (p.Val215Leu) and does not meet the VCEP BP7 criteria. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.139. BayesDel score = -0.503783. HCI prior probability for pathogenicity = 0.0008. MAPP score = 2.5. Custom PP2 score = 0.0.
9 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 25070057 ↗Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.Giardiello FM et al. · 2014Multi-Society Task Force consensus guidelines on genetic evaluation and management of Lynch syndrome. This is a clinical practice guideline; NM_000179.3:c.643G>C is not mentioned.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.This is the ACMG/AMP standards and guidelines for sequence variant interpretation. NM_000179.3:c.643G>C is not mentioned in this paper.Does not name this variant
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PMID 28135145 ↗Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.Yurgelun MB et al. · 2017Yurgelun et al. (2017) evaluated germline cancer susceptibility gene mutations in 1,058 individuals with colorectal cancer. NM_000179.3:c.643G>C was not identified among the reported variants.Does not name this variant
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PMID 23408351 ↗Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts.Revised European guidelines (Mallorca group) for clinical management of Lynch syndrome. NM_000179.3:c.643G>C is not mentioned in this paper.Does not name this variant
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PMID 24310308 ↗ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis).ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer. This is a laboratory standards document; NM_000179.3:c.643G>C is not mentioned.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional VersiPDQ Cancer Genetics Risk Assessment and Counseling summary. No abstract or full text available for review. Given the nature of this resource as a broad clinical summary, the specific variant NM_000179.3:c.643G>C is not expected to be mentioned.Does not name this variant
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PMID 27854360 ↗Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.ACMG SF v2.0 recommendations for reporting secondary findings in clinical exome and genome sequencing. NM_000179.3:c.643G>C is not mentioned in this policy statement.Does not name this variant
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PMID 30267214 ↗Rare loss of function variants in candidate genes and risk of colorectal cancer.Rosenthal EA et al. · 2018Rosenthal et al. (2018) evaluated rare loss-of-function variants in 158 candidate genes for colorectal cancer risk. A c.643C>T variant in RECQL (not MSH6) was observed, but NM_000179.3:c.643G>C was not identified.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp et al. (2017) describe Sherloc, a refinement of the ACMG-AMP variant classification criteria. NM_000179.3:c.643G>C is not mentioned in this methods paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,610,788 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.090
Open source ↗
ClinVar
3 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/628619/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48025765-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47798626-G-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47798626-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.643G…
- OncoKB ↗www.oncokb.org/gene/MSH6/V215L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.643G%3EC
- 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= 1.24163e-06; MAF= 0.00012%, 2/1610788 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22727e-05; MAF= 0.00223%, 1/44898 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.05108e-06; MAF= 0.00041%, 1/246848 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.87737e-06; MAF= 0.00089%, 1/112646 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 628619)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.139. BayesDel score = -0.503783. HCI prior probability for pathogenicity = 0.0008. MAPP score = 2.5. Custom PP2 score = 0.0.
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.