About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.836G>A, p.(Ser279Asn)
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
Absent from gnomAD v4.1 (0 alleles), meeting the MSH6 VCEP PM2_Supporting allele frequency threshold of <0.00002 (<1 in 50,000 alleles).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
HCI prior probability for pathogenicity is 0.0075, which is below the MSH6 VCEP BP4_Supporting threshold of <0.11 for missense variants. Multiple lines of computational evidence suggest no deleterious impact.
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, BP4 supporting benign; 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.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV113286823, 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: 2 met · 13 not met · 0 not assessed · 11 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.836G>A (p.Ser279Asn) is a missense variant in MSH6 exon 4 that is absent from gnomAD v2.1 and v4.1, meeting the VCEP PM2_Supporting criterion (allele frequency <0.00002).
Computational in silico predictors, including the MSH6-specific HCI prior probability of 0.0075, are consistent with a benign impact, meeting the VCEP BP4_Supporting criterion (HCI prior <0.11). SpliceAI predicts no splicing alteration (max delta score 0.00). REVEL score is 0.322 and BayesDel is -0.109.
No functional assay data, segregation data, de novo observations, tumor phenotype data, or same-residue pathogenic comparator variants are available for this variant. The variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories; ClinVar ID 234915) and has been observed once in somatic cancers (COSMIC COSV113286823).
Per the MSH6 VCEP v2.0.0 combination rules: PM2_Supporting (1 pathogenic supporting point) and BP4_Supporting (1 benign supporting point) are equivocal, resulting in a final classification of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingAbsent from gnomAD v4.1 (0 alleles), meeting the MSH6 VCEP PM2_Supporting allele frequency threshold of <0.00002 (<1 in 50,000 alleles). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent. Allele frequency 0.0
- below VCEP PM2_Supporting cutoff of 0.00002.
Sources
BP4 SupportingHCI prior probability for pathogenicity is 0.0075, which is below the MSH6 VCEP BP4_Supporting threshold of <0.11 for missense variants. Multiple lines of computational evidence suggest no deleterious impact. Details ▾Hide ▴
Evidence considered
- HCI prior: 0.0075 (<0.11 BP4_Supporting threshold). SpliceAI max delta: 0.00 (no splicing impact). REVEL: 0.322. BayesDel: -0.109.
Sources
Not met · 13 · evaluated, threshold not reached
PS1 No alternate nucleotide change at codon 279 encoding p.Ser279Asn has been classified as Pathogenic by the MSH6 VCEP. Details ▾Hide ▴
PS2 No de novo occurrences with confirmed parentage have been reported for NM_000179.3:c.836G>A. Details ▾Hide ▴
Evidence considered
- Exploratory literature and database search found zero de novo reports for this variant.
Still missing
- No published de novo observations with confirmed parentage.
PS3 No calibrated functional assay data with functional odds for pathogenicity are available for this variant. The VCEP functional assay documentation does not include c.836G>A. Details ▾Hide ▴
Evidence considered
- VCEP functional assay spreadsheet searched
- variant not listed. Exploratory search found no variant-specific functional studies.
Still missing
- No functional assay data (MMR activity
- protein expression
- or interaction assays) for p.Ser279Asn.
Sources
vcep_functional_assay_svi_documentation_mmr
PM5 No missense variant at codon 279 has been classified as Pathogenic or Likely Pathogenic on the protein level by the MSH6 VCEP; PM5 requires an established P/LP comparator at the same residue. Details ▾Hide ▴
PP1 No cosegregation data with computed Bayes Likelihood Ratio are available for this variant. Details ▾Hide ▴
Evidence considered
- No published pedigree or cosegregation analyses identified for c.836G>A.
Still missing
- No family cosegregation data available.
PP3 HCI prior probability 0.0075 does not meet VCEP missense thresholds (>0.68 for PP3_Supporting, >0.81 for PP3_Moderate). SpliceAI max delta score 0.00 does not meet the non-canonical splice threshold (>=0.2). Details ▾Hide ▴
Evidence considered
- HCI prior: 0.0075 (thresholds: >0.68 Supporting
- >0.81 Moderate). SpliceAI max delta: 0.00 (threshold: >=0.2 Supporting). REVEL: 0.322. BayesDel: -0.109.
Sources
PP4 No MSI-H tumor data or MMR protein expression loss data consistent with the variant location have been reported for c.836G>A. Details ▾Hide ▴
Evidence considered
- PP4 requires MSI-H tumors and/or MMR protein expression loss
- no such data identified for this variant.
Still missing
- No tumor phenotype (MSI/IHC) data available for carriers of this variant.
Sources
BA1 Absent from gnomAD v4.1; does not meet the VCEP BA1 Stand-Alone threshold of Grpmax filtering AF >= 0.0022 (0.22%). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: absent (AF 0.0)
- BA1 threshold >=0.0022 not met.
Sources
BS1 Absent from gnomAD v4.1; does not meet the VCEP BS1 Strong threshold of Grpmax filtering AF >= 0.00022 (0.022%). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: absent (AF 0.0)
- BS1 threshold >=0.00022 not met.
Sources
BS2 No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with CRC after age 45 without CMMRD features. Details ▾Hide ▴
Evidence considered
- No reported trans observations with confirmed phase meeting VCEP BS2 criteria.
Still missing
- No trans co-occurrence data available.
Sources
BS3 No calibrated functional assay data showing functional odds for pathogenicity <= 0.48 for this variant. The VCEP functional assay documentation does not include c.836G>A. Details ▾Hide ▴
Evidence considered
- VCEP functional assay spreadsheet searched
- variant p.Ser279Asn not evaluated. No benign functional evidence identified.
Still missing
- No functional assay demonstrating proficient MMR activity for p.Ser279Asn.
Sources
vcep_functional_assay_svi_documentation_mmrcspec ↗
BS4 No lack-of-segregation data with computed Bayes Likelihood Ratio are available for this variant. Details ▾Hide ▴
Evidence considered
- No published non-segregation analyses identified for c.836G>A.
Still missing
- No family non-segregation data available.
Sources
BP5 No MSS tumor data or MMR protein expression data demonstrating inconsistent MMR protein loss have been reported for this variant. Details ▾Hide ▴
Evidence considered
- BP5 requires MSS tumors or inconsistent MMR protein loss
- no such clinical tumor data identified for c.836G>A.
Still missing
- No tumor phenotype (MSS/IHC) data available.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant p.(Ser279Asn); does not meet any MSH6 VCEP v2.0.0 PVS1 null-variant criteria (not nonsense, frameshift, canonical splice, initiation codon, or exon-level deletion). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- PVS1 applies only to null variants per VCEP decision tree.
Sources
pvs1_gene_contextpvs1_variant_assessment
PS4 VCEPThis criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification. Details ▾Hide ▴
PM1 VCEPThis criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification. Details ▾Hide ▴
PM6 VCEPThis criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification. Details ▾Hide ▴
PP2 VCEPThis criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification. Details ▾Hide ▴
PP5 VCEPThis criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification. Details ▾Hide ▴
BP1 VCEPThis criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification. Details ▾Hide ▴
BP2 VCEPThis criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification. Details ▾Hide ▴
BP6 VCEPThis criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/AMissense variant c.836G>A (p.Ser279Asn); BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions per VCEP specification. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous or intronic. SpliceAI max delta 0.00 confirms no cryptic splice effect
- but BP7 is structurally not applicable.
Sources
PS5 N/APS5 is not included in the MSH6 VCEP v2.0.0 specification and is not used in this framework. Details ▾Hide ▴
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.836G>A
- Protein (HGVS p.)
- NP_000170.1:p.(Ser279Asn)
- GRCh38
- chr2:47798819 G>A
- GRCh37
- chr2:48025958 G>A
- ClinVar
- 1779224, 1770847, 1284533, 234915
- COSMIC
- COSV113286823
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.322
- BayesDel
- -0.109
How the predictions were used
BP4 SupportingHCI prior probability for pathogenicity is 0.0075, which is below the MSH6 VCEP BP4_Supporting threshold of <0.11 for missense variants. Multiple lines of computational evidence suggest no deleterious impact. Details ▾Hide ▴
Evidence considered
- HCI prior: 0.0075 (<0.11 BP4_Supporting threshold). SpliceAI max delta: 0.00 (no splicing impact). REVEL: 0.322. BayesDel: -0.109.
Sources
PP3 HCI prior probability 0.0075 does not meet VCEP missense thresholds (>0.68 for PP3_Supporting, >0.81 for PP3_Moderate). SpliceAI max delta score 0.00 does not meet the non-canonical splice threshold (>=0.2). Details ▾Hide ▴
Evidence considered
- HCI prior: 0.0075 (thresholds: >0.68 Supporting
- >0.81 Moderate). SpliceAI max delta: 0.00 (threshold: >=0.2 Supporting). REVEL: 0.322. BayesDel: -0.109.
Sources
BP7 N/AMissense variant c.836G>A (p.Ser279Asn); BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions per VCEP specification. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous or intronic. SpliceAI max delta 0.00 confirms no cryptic splice effect
- but BP7 is structurally not applicable.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.322. BayesDel score = -0.109362. HCI prior probability for pathogenicity = 0.0075. MAPP score = 5.62. Custom PP2 score = 0.093.
1 paper record 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.
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 0.000
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/234915/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48025958-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47798819-G-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.836G…
- OncoKB ↗www.oncokb.org/gene/MSH6/S279N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124987486
- 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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 234915)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.322. BayesDel score = -0.109362. HCI prior probability for pathogenicity = 0.0075. MAPP score = 5.62. Custom PP2 score = 0.093.
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; COSV113286823, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.