About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.3162C>T, p.(Ile1054=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign 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 v2.0.0. 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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BS1Strong
BS1 · strong
gnomAD v4.1 grpmax filtering allele frequency is 0.00058972 (0.059%), which falls within the VCEP BS1 range of ≥ 0.00022 (0.022%) and < 0.0022 (0.22%). This allele frequency is inconsistent with a fully penetrant dominant disorder, meeting BS1 at Strong strength.
BP4Supporting
BP4 · supporting
Synonymous variant with SpliceAI max delta score of 0.03, which is ≤ 0.1. Under VCEP BP4 rules, synonymous variants with SpliceAI delta ≤ 0.1 meet BP4_Supporting as they are predicted to have no splicing impact.
BP7Supporting
BP7 · supporting
NM_000179.3:c.3162C>T is a synonymous variant in exon 4, located 10 bases upstream of the 3' exon boundary (c.3172), which satisfies the VCEP BP7 requirement of being at or beyond +7 from the 3' splice site. SpliceAI predicts no splicing impact (delta 0.03), supporting no effect on splicing.
Recorded classification: Likely benign
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 Rule19 (Benign.Supporting >=2) with applied criteria: BS1 strong benign, BP4 supporting benign, BP7 supporting benign; maps to Likely Benign.
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
79 / 1,610,432 alleles
gnomAD v4.1: 79 / 1,610,432 alleles. Recorded AF 4.90552e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000104609; MAF= 0.01046%, 29/277224 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000895547; MAF= 0.08955%, 22/24566 alleles, homozygotes = 0); grpmax FAF= 0.00063248.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52282023, n = 1 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: 3 met · 11 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_000179.3:c.3162C>T (p.Ile1054=) is a synonymous variant in exon 4 of MSH6 with a gnomAD v4.1 grpmax filtering allele frequency of 0.059% (79/1,610,432 alleles), meeting VCEP BS1 at Strong strength.
SpliceAI predicts no splicing impact for this synonymous variant (max delta score 0.03), meeting VCEP BP4 at Supporting strength.
The variant is synonymous and located beyond the splice consensus region in exon 4, meeting VCEP BP7 at Supporting strength.
ClinVar classifies this variant as Benign/Likely benign (Variation ID 184018, review status: criteria provided, multiple submitters, no conflicts).
No pathogenic criteria are met for this variant. Under VCEP InSiGHT MMR v2.0.0 classification rules, one Benign Strong criterion (BS1) plus one or more Benign Supporting criteria (BP4, BP7) yields a classification of Likely Benign (Rule 18).
No criteria match.
Met · 3
BS1 StronggnomAD v4.1 grpmax filtering allele frequency is 0.00058972 (0.059%), which falls within the VCEP BS1 range of ≥ 0.00022 (0.022%) and < 0.0022 (0.22%). This allele frequency is inconsistent with a fully penetrant dominant disorder, meeting BS1 at Strong strength. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 0.00058972 (79/1
- 610
- 432 alleles)
- VCEP BS1 range = 0.00022-0.0022
Sources
BP4 SupportingSynonymous variant with SpliceAI max delta score of 0.03, which is ≤ 0.1. Under VCEP BP4 rules, synonymous variants with SpliceAI delta ≤ 0.1 meet BP4_Supporting as they are predicted to have no splicing impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.03 (<= 0.1 threshold for no splicing impact)
Sources
BP7 SupportingNM_000179.3:c.3162C>T is a synonymous variant in exon 4, located 10 bases upstream of the 3' exon boundary (c.3172), which satisfies the VCEP BP7 requirement of being at or beyond +7 from the 3' splice site. SpliceAI predicts no splicing impact (delta 0.03), supporting no effect on splicing. Details ▾Hide ▴
Evidence considered
- Synonymous variant c.3162C>T at position -10 from 3' exon boundary
- SpliceAI delta 0.03
Sources
Not met · 11 · evaluated, threshold not reached
PS2 No de novo observations identified in ClinVar submissions, published literature, or other evidence sources for NM_000179.3:c.3162C>T. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 184018: no de novo submissions reported
Still missing
- No de novo testing data available
Sources
PS3 No calibrated functional assay data identified for this variant in the VCEP MMR functional assay documentation spreadsheet or in the published literature. This synonymous variant has not been assessed in MMR functional assays. Details ▾Hide ▴
Evidence considered
- VCEP functional assay spreadsheet contains no entry for c.3162C>T or p.Ile1054=
Still missing
- No functional assay data for this synonymous variant
Sources
vcep_functional_assay_svi_documentation_mmr
PM2 PM2_Supporting threshold under the VCEP requires absence or extreme rarity with gnomAD v4 allele frequency below 0.00002 (<1 in 50,000 alleles). This variant has a gnomAD v4.1 allele frequency of 0.000049 (79/1,610,432 alleles), which exceeds the PM2 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 0.000049 (79/1
- 610
- 432 alleles)
- PM2 VCEP cutoff = <0.00002
Sources
PP1 No co-segregation data available in published literature or ClinVar submissions for NM_000179.3:c.3162C>T. Details ▾Hide ▴
Evidence considered
- No segregation pedigrees identified for this variant
Still missing
- No family segregation studies available
Sources
PP3 Synonymous variant; VCEP PP3 rules for missense variants require HCI prior >0.68, which is not applicable (synonymous changes are not in the HCI missense prior table). The synonymous/intronic splice prediction rule requires SpliceAI delta >= 0.2; this variant has a max SpliceAI delta of 0.03, well below the threshold. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.03 (< 0.2 threshold)
- HCI prior not applicable for synonymous variant
Sources
PP4 No tumor MSI or immunohistochemistry data available for this variant. VCEP PP4 requires MSI-H tumor findings and/or loss of MMR protein expression consistent with variant location. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data provided for this variant
Still missing
- No tumor MSI/IHC data available
Sources
BA1 VCEP BA1 threshold requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0022 (0.22%). The grpmax FAF for this variant is 0.00058972 (0.059%), which does not meet the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 0.00058972
- VCEP BA1 cutoff = >=0.0022
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. BS2 requires confirmation of phase through parental or offspring testing. Details ▾Hide ▴
Evidence considered
- No trans co-occurrence data available
Still missing
- No phase-confirmed co-occurrence data
Sources
BS3 No calibrated functional assay data identified for this variant in the VCEP MMR functional assay documentation. BS3 requires calibrated functional assays with functional odds for pathogenicity ≤ 0.05 (Strong) or >0.05 & ≤0.48 (Supporting), or variant-specific proficient function in MMR laboratory assays. Details ▾Hide ▴
Evidence considered
- VCEP functional assay spreadsheet contains no entry for c.3162C>T
Still missing
- No functional data for this synonymous variant
Sources
vcep_functional_assay_svi_documentation_mmr
BS4 No segregation or lack-of-segregation data available for NM_000179.3:c.3162C>T. BS4 requires a combined Bayes Likelihood Ratio < 0.05 (Strong) or > 0.05 & ≤ 0.48 (Supporting) from pedigree analysis. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family segregation data
Sources
BP5 No tumor data available to assess MSS status or MMR protein expression. VCEP BP5 requires CRC/endometrial tumors with MSS and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation findings. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available
Still missing
- No tumor MSI/IHC/MSS data available
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASynonymous variant NP_000170.1:p.(Ile1054=) does not introduce a premature termination codon, affect canonical splice sites, or alter the reading frame. PVS1 is not applicable to silent substitutions under either VCEP MMR or generic ACMG/AMP PVS1 frameworks. Details ▾Hide ▴
Evidence considered
- Synonymous substitution at c.3162C>T
- no null effect on protein
Sources
pvs1_gene_contextpvs1_variant_assessment
PS1 N/ASynonymous variant p.(Ile1054=) does not encode an amino acid change. PS1 requires a missense substitution producing the same amino acid change as a known pathogenic variant. Details ▾Hide ▴
Evidence considered
- Synonymous substitution
- no amino acid change
PS4 VCEPPS4 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0. Details ▾Hide ▴
PM1 VCEPPM1 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0. Details ▾Hide ▴
PM5 N/ASynonymous variant p.(Ile1054=) produces no amino acid change. PM5 requires a missense change at an amino acid residue where a different missense change has been classified as pathogenic. Details ▾Hide ▴
Evidence considered
- Variant class is synonymous
- not missense
- PM5 candidate search returned not_applicable
Sources
pm5_candidates
PM6 VCEPPM6 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0. Details ▾Hide ▴
PP2 VCEPPP2 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0. Details ▾Hide ▴
PP5 VCEPPP5 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0. Details ▾Hide ▴
BP1 VCEPBP1 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0. Details ▾Hide ▴
BP2 VCEPBP2 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0. Details ▾Hide ▴
BP6 VCEPBP6 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
PS5 N/APS5 is not included as an active criterion in the InSiGHT MMR VCEP v2.0.0 framework, and no variant-specific case-control or statistical evidence for this synonymous variant exists. Details ▾Hide ▴
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.3162C>T
- Protein (HGVS p.)
- NP_000170.1:p.(Ile1054=)
- GRCh38
- chr2:47801145 C>T
- GRCh37
- chr2:48028284 C>T
- ClinVar
- 184018
- COSMIC
- COSV52282023
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
79 / 1,610,432 alleles
AF 4.91e-05 · 0 homozygotes · FAF 0.00059
gnomAD v2.1
29 / 277,224 alleles
AF 0.000105 · 0 homozygotes · FAF 0.000632
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 4.9e-05 · 79 / 1,610,432 alleles · 0 hom · FAF 0.00059
| African/African American56 / 75,006 | 0.00075 |
| Middle Eastern1 / 6,062 | 0.00016 |
| East Asian3 / 44,866 | 6.7e-05 |
| Remaining individuals4 / 62,488 | 6.4e-05 |
| European (Finnish)2 / 60,486 | 3.3e-05 |
| Admixed American1 / 59,990 | 1.7e-05 |
| European (non-Finnish)12 / 1,179,956 | 1e-05 |
0 alternate alleles recorded in 3 other groups: Amish, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0001 · 29 / 277,224 alleles · 0 hom · FAF 0.00063
| African/African American22 / 24,566 | 0.0009 |
| East Asian3 / 19,868 | 0.00015 |
| European (Finnish)2 / 21,538 | 9.3e-05 |
| Admixed American1 / 35,368 | 2.8e-05 |
| European (non-Finnish)1 / 127,836 | 7.8e-06 |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.90552e-05; MAF= 0.00491%, 79/1610432 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000746607; MAF= 0.07466%, 56/75006 alleles, homozygotes = 0); grpmax FAF= 0.00058972.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000104609; MAF= 0.01046%, 29/277224 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000895547; MAF= 0.08955%, 22/24566 alleles, homozygotes = 0); grpmax FAF= 0.00063248.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingSynonymous variant with SpliceAI max delta score of 0.03, which is ≤ 0.1. Under VCEP BP4 rules, synonymous variants with SpliceAI delta ≤ 0.1 meet BP4_Supporting as they are predicted to have no splicing impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.03 (<= 0.1 threshold for no splicing impact)
Sources
BP7 SupportingNM_000179.3:c.3162C>T is a synonymous variant in exon 4, located 10 bases upstream of the 3' exon boundary (c.3172), which satisfies the VCEP BP7 requirement of being at or beyond +7 from the 3' splice site. SpliceAI predicts no splicing impact (delta 0.03), supporting no effect on splicing. Details ▾Hide ▴
Evidence considered
- Synonymous variant c.3162C>T at position -10 from 3' exon boundary
- SpliceAI delta 0.03
Sources
PP3 Synonymous variant; VCEP PP3 rules for missense variants require HCI prior >0.68, which is not applicable (synonymous changes are not in the HCI missense prior table). The synonymous/intronic splice prediction rule requires SpliceAI delta >= 0.2; this variant has a max SpliceAI delta of 0.03, well below the threshold. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.03 (< 0.2 threshold)
- HCI prior not applicable for synonymous variant
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
8 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 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.The ACMG/AMP 2015 standards and guidelines for sequence variant interpretation. This foundational framework paper does not discuss individual MSH6 variants.Does not name this variant
-
PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Describes a standardized DNA variant scoring system for Mendelian disorders. No MSH6 variant-specific data are reported.Does not name this variant
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PMID 23788249 ↗ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.Green RC et al. · 2013ACMG recommendations for reporting incidental findings in clinical exome and genome sequencing. Provides a gene list for return of incidental findings including MSH6 but does not discuss specific variants.Does not name this variant
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PMID 24493721 ↗American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.ASCO expert statement on collection and use of cancer family history for oncology providers. No variant-level data are reported.Does not name this variant
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PMID 25711197 ↗Lynch Syndrome: A Primer for Urologists and Panel Recommendations.Mork M et al. · 2015Review of Lynch syndrome for urologists, discussing MMR gene mutations in general. No individual MSH6 variants are reported.Does not name this variant
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PMID 26324357 ↗American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.ASCO policy statement update on genetic and genomic testing for cancer susceptibility. Discusses Lynch syndrome genes at a general level without reporting individual variants.Does not name this variant
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PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ cancer genetics summary on breast and gynecologic cancers. No abstract or full-text content mentioning this MSH6 variant was identified.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc refinement of ACMG-AMP variant classification criteria. Background review reference; no variant-specific data.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
79 / 1,610,432 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
Captured ClinVar source record
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/184018/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48028284-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47801145-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47801145-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.3162…
- OncoKB ↗www.oncokb.org/gene/MSH6/I1054=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124982855
- 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= 4.90552e-05; MAF= 0.00491%, 79/1610432 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000746607; MAF= 0.07466%, 56/75006 alleles, homozygotes = 0); grpmax FAF= 0.00058972.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000104609; MAF= 0.01046%, 29/277224 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000895547; MAF= 0.08955%, 22/24566 alleles, homozygotes = 0); grpmax FAF= 0.00063248.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is present in ClinVar (Variation ID: 184018); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52282023, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.