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This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
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About MSH6
MSH6 encodes a protein in the DNA mismatch repair system, which fixes errors made during DNA replication. Partnering with MSH2, it forms a complex that recognizes and helps correct mismatched DNA bases, keeping the genetic code stable. Inherited mutations in MSH6 cause Lynch syndrome (hereditary nonpolyposis colorectal cancer), raising the risk of colorectal, endometrial, ovarian, and other cancers, while mutations in both copies lead to constitutional mismatch repair deficiency. Because faulty mismatch repair drives tumor development and produces microsatellite instability, MSH6 acts as a tumor suppressor, and cancers with such repair defects often respond well to immune checkpoint inhibitor therapy.
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01The reasoning
How it was classified
The recorded framework is ClinGen MSH6 VCEP v2.0. 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.
ACMG/AMP criteria under ClinGen MSH6 VCEP v2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 9 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
MSH6 VCEP (ClinGen InSiGHT) v2.0 was used as the governing framework in preference to generic ACMG/AMP.
PVS1 not applicable: variant lies at intronic positions -16 to -10, outside the VCEP's required IVS±1/±2 canonical splice window, is not a coding nonsense/frameshift/initiation-codon variant, is not a multi-exon genomic deletion, and SpliceAI shows no predicted splice impact (max delta 0.00); no confirmatory RNA assay data present.
PM4 and BP3 are both explicitly flagged as Not Applicable by the MSH6 VCEP specification, and independently do not apply because the variant does not produce an in-frame protein-length change.
The MSH6 VCEP (ClinGen InSiGHT) CSPEC v2.0 governs this case and explicitly marks PM1, PP2, and BP1 as Not Applicable for MSH6, so these three criteria are not_applicable regardless of variant type.
PS1 and PM5 remain nominally applicable under the CSPEC but both require a missense substitution (same amino acid change / same-residue missense) or, for PS1 only, a non-canonical splice nucleotide comparator with similar-or-worse SpliceAI prediction. This variant, NM_000179.3:c.4002-16_4002-10del, is a deep intronic deletion with unknown protein consequence (p.?), is not missense, and SpliceAI shows no significant splice impact (max delta 0.00), so neither criterion's evidentiary requirements are met.
No variant-specific functional assay, MMR complementation assay, or cDNA/monoallelic expression data for NM_000179.3:c.4002-16_4002-10del is present in this case's evidence bundle; the single associated literature reference (PMID:26467025) is a general variant-scoring methodology paper with no MSH6- or variant-specific functional content.
Both PS3 and BS3 are therefore returned as not_assessed pending laboratory functional/mRNA assay data for this specific variant.
Governing framework: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP specification for MSH6 (cspec v2.0), which defines separate PP3/BP4 pathways for missense (HCI-prior lookup) and for intronic/synonymous (SpliceAI, per Walker et al 2023, PMID 37352859) variants.
This variant is a non-canonical intronic deletion, so only the SpliceAI-based splice-impact pathway applies (the HCI-prior missense pathway is not applicable).
SpliceAI Lookup returned max delta score = 0.00 for this variant, which is below both the PP3 threshold (>=0.2) and satisfies the BP4 threshold (<=0.1), yielding BP4_Supporting and PP3 not met.
BP7 requires the variant to sit at or beyond -21/+7 from the exon boundary; this variant (positions -16 to -10) is within that boundary, so BP7 is not met even though BP4 is met from the same SpliceAI null result.
No criteria match.
Met · 2
PM2SupportingMet (Supporting): gnomAD v4 Grpmax FAF of 5.02e-06 is below the <0.00002 rarity threshold.
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Reasoning
The MSH6 InSiGHT VCEP specifies PM2 at an absent or extremely rare allele frequency below 0.00002 (<1 in 50,000 alleles) in gnomAD v4. This variant has a gnomAD v4 Grpmax FAF of 5.02e-06, total AF of 4.15327e-06 from 6/1,444,646 alleles, and zero homozygotes. The Grpmax FAF is below 0.00002, so PM2 is met at Supporting strength.
Rule
Absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4 dataset.
Evidence considered
The applicable MSH6 VCEP PM2 rule is absent/extremely rare allele frequency <0.00002 in gnomAD v4 and assigns the criterion Supporting strength.
gnomAD v4.1 reports Grpmax FAF 5.02e-06 and total AF 4.15327e-06 (6/1,444,646 alleles), with zero observed homozygotes. The highest population AF is 3.02691e-05 in African/African American individuals, while the VCEP rule uses Grpmax FAF; the qualifying Grpmax value is below 0.00002.
BP4SupportingMet (Supporting): SpliceAI max delta 0.00, below the <=0.1 no-splice-impact threshold for intronic variants.
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Reasoning
The InSiGHT MMR VCEP (MSH6) BP4 rule states that for intronic and synonymous variants, SpliceAI predicting no splicing impact with delta score <= 0.1 satisfies BP4 at Supporting strength (per Walker et al 2023). NM_000179.3:c.4002-16_4002-10del is an intronic (non-canonical, acceptor-region) deletion. SpliceAI Lookup for this exact variant returned a max delta score of 0.00 (well below the <=0.1 threshold), so BP4_Supporting is met via the splice-impact path of this criterion.
Rule
InSiGHT MMR VCEP (MSH6) cspec v2.0 BP4: SpliceAI delta score <= 0.1 for intronic/synonymous variant (Walker et al 2023) met (score = 0.00) -> BP4_Supporting.
Evidence considered
SpliceAI Lookup for NM_000179.3:c.4002-16_4002-10del: max delta score = 0.00, satisfying the VCEP BP4 splice-impact threshold of <=0.1.
InSiGHT MMR VCEP (MSH6) cspec BP4 rule: 'For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.'
PS1Not met: a deep intronic deletion with unknown protein consequence cannot match a known pathogenic missense at the same residue.
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Reasoning
NM_000179.3:c.4002-16_4002-10del is a deep intronic deletion (protein consequence NP_000170.1:p.? / unknown; not a coding missense substitution), so the CSPEC PS1 missense same-amino-acid-change branch cannot apply. The CSPEC also allows PS1 for variants affecting the same non-canonical splice nucleotide as a confirmed/likely pathogenic splice variant with similar or worse SpliceAI in silico prediction; however, SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00), which rules out a 'similar or worse' splicing prediction relative to any pathogenic splice comparator, and no confirmed pathogenic splice variant at this same non-canonical nucleotide position was identified in the case evidence bundle.
Rule
MSH6 VCEP (ClinGen InSiGHT) CSPEC v2.0 PS1
Evidence considered
MSH6 CSPEC v2.0 PS1 rule: Strong applies to a predicted missense substitution encoding the same amino acid change as a VCEP-established Pathogenic missense variant (not a splice defect), or variants affecting the same non-canonical splice nucleotide as a confirmed Pathogenic splice variant with similar or worse SpliceAI prediction; Moderate applies to the analogous comparison against a Likely Pathogenic missense/splice variant.
Variant NM_000179.3:c.4002-16_4002-10del has protein consequence NP_000170.1:p.? (unknown/non-missense), so the missense same-amino-acid-change branch of PS1 does not apply.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00; pangolin_SG=0.017, pangolin_SL=-0.071), which does not meet 'similar or worse' splicing prediction relative to any pathogenic non-canonical splice comparator required by the CSPEC PS1 splice branch.
Still missing
No systematic search of ClinVar/VCEP curated variant lists for other MSH6 variants at the identical non-canonical splice nucleotide position was performed beyond what is captured in this case bundle.
PP3Not met: SpliceAI max delta 0.00 versus the >=0.2 splice-impact threshold.
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Reasoning
NM_000179.3:c.4002-16_4002-10del is a non-canonical intronic deletion (acceptor-region, -16 to -10 relative to the downstream exon). The governing InSiGHT MMR VCEP (MSH6) specification requires, for the splice-impact path of PP3, a predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 (per Walker et al 2023). SpliceAI Lookup for this exact variant returned a max delta score of 0.00 (evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00)'), well below the >=0.2 threshold. The missense HCI-prior path of PP3 does not apply because this variant is not a missense substitution. PP3 is therefore not met.
Rule
InSiGHT MMR VCEP (MSH6) cspec v2.0 PP3: SpliceAI delta score >= 0.2 for non-canonical splice nucleotides (Walker et al 2023) not met (score = 0.00).
Evidence considered
SpliceAI Lookup (spliceailookup.broadinstitute.org) for NM_000179.3:c.4002-16_4002-10del returned max delta score = 0.00, far below the VCEP PP3 splice-impact threshold of >=0.2.
InSiGHT MMR VCEP (MSH6) cspec PP3 rule: 'Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.'
Variant is an intronic deletion, not a missense substitution, so the HCI-prior missense path of PP3 (>0.68 HCI prior) is not applicable.
BA1Not met: gnomAD v4 Grpmax FAF 5.02e-06 (0.000502%) versus the >=0.0022 (0.22%) BA1 threshold.
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Reasoning
The MSH6 InSiGHT VCEP BA1 rule requires a gnomAD v4 Grpmax filtering allele frequency of at least 0.0022 (0.22%) and exclusion as a founder pathogenic variant. The observed gnomAD v4 Grpmax FAF is 5.02e-06 (0.000502%), far below the threshold; therefore BA1 is not met.
Rule
GnomAD v4 Grpmax filtering allele frequency >= 0.0022 (0.22%) and variant is excluded as founder pathogenic variant.
Evidence considered
The applicable MSH6 VCEP specifies BA1 at gnomAD v4 Grpmax FAF >=0.0022 (0.22%), provided the variant is not a founder pathogenic variant.
gnomAD v4.1 reports Grpmax FAF 5.02e-06, with total AF 4.15327e-06 from 6/1,444,646 alleles; the highest population AF is 3.02691e-05 in African/African American individuals (2/66,074 alleles). These values are all below the BA1 threshold.
The MSH6 InSiGHT VCEP BS1 rule requires a gnomAD v4 Grpmax filtering allele frequency from 0.00022 inclusive to below 0.0022 (0.022%-0.22%), with exclusion as a founder pathogenic variant. The observed Grpmax FAF is 5.02e-06 (0.000502%), below the lower bound; therefore BS1 is not met.
Rule
GnomAD v4 Grpmax filtering allele frequency >= 0.00022 and < 0.0022 (0.022-0.22%) and variant is excluded as founder pathogenic variant.
Evidence considered
The applicable MSH6 VCEP specifies BS1 at gnomAD v4 Grpmax FAF >=0.00022 and <0.0022 (0.022%-0.22%), provided the variant is not a founder pathogenic variant.
gnomAD v4.1 reports Grpmax FAF 5.02e-06, which is below 0.00022; the observed population frequency does not reach the BS1 range.
BP7Not met: the intronic deletion at -16 to -10 lies closer to the exon than the required -21 boundary.
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Reasoning
The InSiGHT MMR VCEP (MSH6) BP7 rule requires a synonymous (silent) or intronic variant at or beyond -21/+7 relative to the exon boundary (5'/3'). This variant, NM_000179.3:c.4002-16_4002-10del, is an intronic deletion spanning positions -16 to -10 relative to the downstream exon (acceptor-region, within the polypyrimidine tract/branch-point zone), which is closer to the exon than the -21 boundary and therefore does not satisfy the 'at or beyond -21/+7' positional requirement. It is also not a synonymous variant. BP7 is therefore not met despite the SpliceAI null-impact result already being captured under BP4.
Rule
InSiGHT MMR VCEP (MSH6) cspec v2.0 BP7: intronic/synonymous variant at or beyond -21/+7 not met (variant at -16 to -10, inside the -21 boundary).
Evidence considered
InSiGHT MMR VCEP (MSH6) cspec BP7 rule: 'A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.'
Variant position (c.4002-16 to c.4002-10) falls within -21 of the exon boundary, not beyond it, so the BP7 positional criterion is not satisfied; variant is not synonymous.
PS2Not assessed: no de novo observation, parental testing, or qualifying tumor evidence was available.
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Reasoning
The MSH6 InSiGHT VCEP framework applies PS2 using de novo points based on confirmed maternity/paternity and Lynch-syndrome-spectrum tumor evidence. The case-evidence bundle contains no proband-level de novo observation, parental testing, maternity/paternity confirmation, or qualifying tumor evidence for this variant; therefore no PS2 points can be assigned.
Rule
MSH6 InSiGHT VCEP PS2: >=4 de novo points = Very Strong; 2-3.5 points = Strong; 1-1.5 points = Moderate; 0.5 points = Supporting. Points require the specified proband, parental-confirmation, and tumor-context evidence.
Evidence considered
The MSH6 InSiGHT VCEP specifies PS2 as applicable and assigns 2 points when both maternity and paternity are confirmed with an MMR-deficient Lynch-syndrome-spectrum tumor, 1 point when both parents are confirmed without tumor data, and 0.5 points when de novo status is assumed with incomplete parental confirmation.
The case bundle provides no proband or family de novo data. The ClinVar record reports the condition as not provided and variant origin as unknown, with no parental or tumor evidence recorded.
Still missing
Proband-level documentation that the variant is de novo
Parental testing and confirmation of maternity and paternity
PS3Not assessed: no variant-specific functional assay or mRNA expression data was available.
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Reasoning
The MSH6 VCEP (InSiGHT Hereditary Colorectal Cancer/Polyposis EP, cspec v2.0) requires calibrated functional assay odds-of-pathogenicity (>18.7 Strong, >4.3-18.7 Moderate, >2.08-4.3 Supporting), or an MMR function defect per the VCEP functional assay flowchart, or documented monoallelic expression (<10% wild-type allele in cDNA without puromycin, with/without NMD block) to apply PS3. This case's evidence bundle (evidence.json, prefetch.json, vcep_materials.json) contains no variant-specific functional assay results, no MMR functional assay flowchart outcome, and no cDNA/monoallelic expression data for NM_000179.3:c.4002-16_4002-10del. The only literature hit (PMID:26467025) is a general DNA variant scoring methodology paper (Quest Diagnostics DVS system) with no MSH6-specific or variant-specific functional data and does not mention this variant. No functional evidence is available to assess PS3.
Still missing
No calibrated MMR functional assay (e.g. cell-based complementation, in vitro MMR activity) results reported for this variant
No MSH6 mRNA/cDNA monoallelic expression or NMD-block splicing assay data available for this variant
No source in this case's evidence bundle addresses MMR function defect status per the VCEP functional assay flowchart
PM3Not assessed: no second MSH6 variant, phase, or family-testing evidence was available.
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Reasoning
The MSH6 InSiGHT VCEP specification makes PM3 applicable when the variant co-occurs with a known pathogenic or likely pathogenic variant in MSH6 in a patient with clinical features consistent with constitutional mismatch repair deficiency. It assigns 1.0 point for the other variant confirmed in trans and 0.5 point when phase is unknown, with strength determined from the summed points. The case-evidence bundle contains no affected-proband observation, second pathogenic/likely pathogenic MSH6 variant, zygosity, phase, or family-testing evidence for this variant; therefore no PM3 points can be assigned.
Rule
Co-occurrence with a known pathogenic/likely pathogenic sequence variant in the same gene in a patient with clinical features consistent with CMMRD; pathogenic/likely pathogenic in trans = 1.0 point, phase unknown = 0.5 point; sum cases to determine strength (>=4 points very strong, 2-3.5 strong, 1-1.5 moderate, 0.5 supporting).
Evidence considered
The governing MSH6 InSiGHT VCEP Version 2.0 framework specifies PM3 as applicable for co-occurrence with a known pathogenic/likely pathogenic variant in the same gene in a patient with CMMRD-consistent clinical features; a confirmed trans configuration is worth 1.0 point and unknown phase is worth 0.5 point.
The consolidated case-evidence bundle provides no allelic co-occurrence, affected-proband, zygosity, phase, or inheritance observation for NM_000179.3:c.4002-16_4002-10del.
Still missing
Affected-proband or case-level clinical evidence consistent with CMMRD is not available.
No known pathogenic or likely pathogenic variant in the same MSH6 patient is documented.
No phase information or parental/offspring testing is documented to establish trans or cis configuration.
PP1Not assessed: no pedigree or cosegregation data was available to quantify a Bayes likelihood ratio.
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Reasoning
The MSH6 InSiGHT VCEP requires cosegregation data quantified with a combined Bayes likelihood ratio. The case-evidence bundle contains no pedigree, affected or unaffected relative genotypes, meioses, segregation observations, or Bayes likelihood ratio, so PP1 cannot be assigned.
Rule
MSH6 InSiGHT VCEP PP1: Supporting for combined Bayes likelihood ratio >2.08 and <=4.3; Moderate for >4.3 and <=18.7; Strong for >18.7 in >=2 families.
Evidence considered
The MSH6 InSiGHT VCEP specifies PP1 Supporting for a combined Bayes likelihood ratio >2.08 and <=4.3, Moderate for >4.3 and <=18.7, and Strong for >18.7 in at least two families.
No pedigree or segregation observations are present in the case-evidence bundle. The ClinVar submission lists the condition as not provided and origin as unknown, without family or segregation data.
Still missing
Pedigree with phenotypic status and genotypes of informative relatives
Number of informative meioses and phase confirmation
Combined Bayes likelihood ratio or sufficient data to calculate it
PP4Not assessed: no patient or family phenotype, MSI tumor, or MMR protein-expression data was available.
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Reasoning
PP4 is applicable under the MSH6 V2.0 specification, but the case bundle contains no patient or family phenotype data, no MSI-H tumor results, and no MSH6-consistent loss of MMR protein expression. Therefore, no PP4 strength can be assigned.
Rule
PP4 Supporting: 1 CRC/endometrial MSI-H tumor using a standard marker panel or tumor genome and/or loss of MMR protein expression consistent with the variant location; Moderate: 2 independent tumors; Strong: at least 3 independent tumors in at least 2 families. MSI-H tumors with inconsistent protein expression do not qualify.
Evidence considered
The MSH6 V2.0 PP4 rule requires one or more qualifying CRC/endometrial MSI-H tumors and/or MMR protein loss consistent with the variant location; the bundle provides none of these observations.
Still missing
Patient/family phenotype information is absent.
Tumor MSI testing results and the marker panel used are absent.
Tumor MMR immunohistochemistry or tumor-genome results, including MSH6 consistency, are absent.
BS2Not assessed: no clinical co-occurrence, phase, or age evidence was available.
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Reasoning
The MSH6 VCEP BS2 rule requires confirmed in-trans co-occurrence with a known pathogenic sequence variant in the same gene in an appropriately aged patient with colorectal cancer or another Lynch-syndrome cancer, without CMMRD manifestations, and phase confirmation through parental or offspring testing. The case bundle contains no such clinical co-occurrence, phase, age, or unaffected-individual evidence, so BS2 cannot be assessed.
Rule
Co-occurrence in trans with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 (or another Lynch-syndrome cancer above the median age of onset), without prior or current evidence of CMMRD; phase must be confirmed by testing parents or offspring.
Evidence considered
The applicable MSH6 VCEP restricts BS2 to a qualifying in-trans co-occurrence observation with phase confirmation and clinical criteria; no such observation is present in the consolidated case-evidence bundle.
Still missing
No documented in-trans co-occurrence with a known pathogenic MSH6 variant.
No confirmed parental or offspring testing establishing phase.
No clinical age, cancer phenotype, or CMMRD-exclusion data for a qualifying BS2 observation.
BS3Not assessed: no calibrated wet-lab functional or mRNA assay data was available; computational SpliceAI predictions do not qualify.
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Reasoning
The MSH6 VCEP (cspec v2.0) requires calibrated functional assay odds-of-pathogenicity ≤0.05 (Strong) or >0.05-0.48 (Supporting), or documented absence of mRNA aberration (splicing/allelic imbalance) under NMD-inhibited conditions, or variant-specific proficient function in protein/mRNA-based assays per the MMR functional assay flowchart to apply BS3. No such functional or mRNA-based assay data for NM_000179.3:c.4002-16_4002-10del is present anywhere in this case's evidence bundle (evidence.json, prefetch.json, vcep_materials.json, literature_pass.json). SpliceAI in silico prediction (max delta = 0.00) is a computational tool, not a laboratory functional assay, and cannot be used to satisfy this VCEP's BS3 rule, which explicitly requires calibrated wet-lab functional data. No functional evidence is available to assess BS3.
Still missing
No calibrated MMR functional assay (functional odds for pathogenicity) results reported for this variant
No laboratory mRNA assay (with NMD inhibition) demonstrating absence of splicing aberration or allelic imbalance for this variant
No MMR functional assay flowchart outcome available in the case bundle
BS4Not assessed: no pedigree or segregation observations were available to demonstrate lack of cosegregation.
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Reasoning
The MSH6 InSiGHT VCEP requires quantified lack of cosegregation using a combined Bayes likelihood ratio. The case-evidence bundle contains no unaffected carrier observations, affected non-carrier observations, pedigree, informative meioses, or Bayes likelihood ratio; therefore BS4 cannot be assigned.
Rule
MSH6 InSiGHT VCEP BS4: Strong for combined Bayes likelihood ratio <0.05; Supporting for >0.05 and <=0.48.
Evidence considered
The MSH6 InSiGHT VCEP specifies BS4 Strong for a combined Bayes likelihood ratio <0.05 and BS4 Supporting for a value >0.05 and <=0.48.
No non-segregation observations or family data are present in the case-evidence bundle. The ClinVar submission lists the condition as not provided and origin as unknown, without family segregation information.
Still missing
Documented non-segregation in informative affected or unaffected relatives
Pedigree and relative genotype/phenotype data
Combined Bayes likelihood ratio or sufficient data to calculate it
BP5Not assessed: no qualifying tumor observations (MSI, MMR expression, BRAF/MLH1 methylation) were available.
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Reasoning
BP5 is applicable under the MSH6 V2.0 specification, but the case bundle contains no qualifying tumor observations. There is no evidence of two or more MSS or MMR-protein-preserved tumors, inconsistent MMR protein loss in an LS-spectrum tumor, or BRAF V600E/MLH1 methylation findings.
Rule
BP5 Supporting: 2 or 3 qualifying tumors or 1 BRAF V600E/MLH1 methylation result; Strong: at least 4 qualifying tumors or at least 2 BRAF V600E/MLH1 methylation results, as specified for MSH6.
Evidence considered
The MSH6 V2.0 BP5 rule requires qualifying tumor evidence: 2 or 3 tumors for supporting or at least 4 tumors for strong, or specified BRAF V600E/MLH1 methylation findings; none is documented in the case bundle.
Still missing
Tumor-by-tumor MSI/MSS results are absent.
Tumor MMR immunohistochemistry results are absent.
BRAF V600E and MLH1 methylation results, where relevant, are absent.
Not applicable · 12· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: a deep intronic 7-bp deletion outside the canonical splice sites, with SpliceAI max delta 0.00, does not meet any loss-of-function rule branch.
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Reasoning
MSH6 VCEP (ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis EP, v2.0) restricts PVS1 to: (1) nonsense/frameshift PTC ≤ codon 1341 (or moderate 1342-1360), (2) large genomic alterations of ≥ 1 exon, (3) initiation codon variants, (4) variants at the canonical splice positions IVS±1 or IVS±2, or (5) confirmed splicing aberration by patient-derived mRNA assay. NM_000179.3:c.4002-16_4002-10del is a 7-bp deletion within a deep intronic poly-T tract at positions -16 to -10 relative to the downstream exon, well outside the canonical IVS±1/±2 donor/acceptor dinucleotides required to trigger the VCEP's splice-based PVS1 pathway. It is not a nonsense/frameshift coding variant, not a whole-exon/multi-exon genomic deletion, and not an initiation-codon variant. SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00 across donor/acceptor gain/loss), and no patient-derived RNA/minigene assay evidence is present in the case bundle to invoke the confirmed-splice-aberration pathway. Protein consequence is annotated p.? (unknown/not predicted to alter protein). None of the VCEP PVS1 rule branches are met, so PVS1 is not applicable to this variant.
Rule
MSH6 VCEP PVS1 (cspec v2.0) - variant is deep intronic (c.4002-16_4002-10, i.e. -16 to -10), not at IVS±1/±2, not nonsense/frameshift, not large genomic alteration, not initiation codon; no confirmed RNA splicing aberration on file.
Evidence considered
MSH6 VCEP v2.0 PVS1 rule requires nonsense/frameshift PTC, large genomic alteration, initiation codon variant, or variants specifically at IVS±1/IVS±2 (with NMD prediction) or confirmed mRNA splicing aberration; this deep-intronic deletion at c.4002-16_4002-10 does not fall at the canonical ±1/±2 splice positions.
SpliceAI evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).'
Normalization protein annotation is NP_000170.1:p.? (no predicted protein-level consequence assigned).
Still missing
No patient-derived RNA/minigene splicing assay data available to rule out a low-level cryptic splicing effect despite negative SpliceAI prediction.
PM1VCEPNot applicable: the MSH6 VCEP specification designates PM1 as not applicable for this gene.
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Reasoning
The governing MSH6 VCEP (ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel) CSPEC v2.0 explicitly designates PM1 as 'Not Applicable' for this gene, so PM1 is not assessed further under the VCEP-specific framework and no generic ACMG fallback for PM1 is used per specification precedence.
PM4VCEPNot applicable: designated by the MSH6 VCEP, and the intronic deletion has no in-frame protein consequence.
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Reasoning
The MSH6 VCEP specification (cspec v2.0) explicitly designates PM4 (protein length changes due to in-frame indels in a non-repeat region, or stop-loss) as Not Applicable for this gene. Independent of the VCEP override, this variant is intronic (c.4002-16_4002-10del) with no predicted in-frame protein consequence (protein annotation NP_000170.1:p.?, SpliceAI max delta = 0.00), so a PM4 in-frame protein-length assessment is not scientifically applicable in any case.
VCEP rule
MSH6 VCEP cspec v2.0: PM4 applicability = Not Applicable.
Evidence considered
MSH6 VCEP v2.0 lists PM4 with applicability: 'Not Applicable' for this gene, overriding generic ACMG PM4 usage.
Variant is deep intronic with no in-frame protein-length change predicted; SpliceAI shows no splice impact (max delta score = 0.00), consistent with no altered transcript/protein length.
PM5N/ANot applicable: a deep intronic deletion with unknown protein consequence is not a missense change eligible for same-residue comparison.
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Reasoning
The CSPEC PM5 rule applies only to a missense change at an amino acid residue where a different missense change was classified Pathogenic/Likely Pathogenic by the VCEP on the protein level. This variant is a deep intronic deletion with protein consequence NP_000170.1:p.? (not a missense substitution at a defined residue), and the case's PM5 candidate-collection artifact explicitly flags the variant as not eligible for the classic same-residue missense PM5 search because its consequence class is not missense.
Rule
MSH6 VCEP (ClinGen InSiGHT) CSPEC v2.0 PM5
Evidence considered
MSH6 CSPEC v2.0 PM5 rule requires a missense change at an amino acid residue where a different missense change was classified Pathogenic (Moderate) or Likely Pathogenic (Supporting) by the VCEP on the protein level, and not due to aberrant splicing.
pm5_candidates.json recommendation: pm5_mode is classic_same_residue_missense, eligible_for_classic_pm5_search=false, summary states the variant consequence class (unknown) is not missense, so PM5 should not be applied from this artifact alone.
Variant protein annotation is NP_000170.1:p.? (unknown), consistent with a non-coding/intronic deletion rather than a residue-level missense substitution.
Still missing
If further transcript/splicing analysis later establishes a specific altered residue or reading-frame consequence for this deletion, PM5 eligibility should be re-evaluated.
PP2VCEPNot applicable: designated by the MSH6 VCEP, and the variant is intronic rather than missense.
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Reasoning
The governing MSH6 VCEP CSPEC v2.0 explicitly designates PP2 as 'Not Applicable' for this gene, so PP2 is not assessed further and no generic ACMG missense-constraint fallback is used per specification precedence. Independently, this variant is a deep intronic deletion, not a missense substitution, so PP2's missense-rarity rationale would not apply regardless.
PP5VCEPNot applicable: designated by the MSH6 VCEP, and the ClinVar record holds only a single-submitter uncertain assertion.
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Reasoning
The applicable InSiGHT/ClinGen MSH6 V2.0 specification explicitly designates PP5 as not applicable. In addition, the exact ClinVar record has only a single-submitter uncertain-significance assertion and no expert-panel submission, so it cannot trigger PP5.
VCEP rule
PP5: Not Applicable under the MSH6 V2.0 specification; an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification would be required by the adjudication instructions, and none is present.
Evidence considered
The governing MSH6 V2.0 specification lists PP5 as not applicable.
The exact ClinVar record for NM_000179.3:c.4002-16_4002-10del is Uncertain significance with criteria provided by a single laboratory; expert-panel submissions are absent.
BP1VCEPNot applicable: the MSH6 VCEP specification designates BP1 as not applicable for this gene.
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Reasoning
The governing MSH6 VCEP CSPEC v2.0 explicitly designates BP1 as 'Not Applicable' for this gene, so BP1 is not assessed further and no generic ACMG fallback is used per specification precedence.
BP2VCEPNot applicable: the MSH6 VCEP designates BP2 as not applicable; BS2 is used instead.
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Reasoning
The governing MSH6 InSiGHT VCEP Version 2.0 specification marks BP2 as not applicable and explicitly states that BS2 is used instead. BP2 is therefore not applied in this group, irrespective of whether cis/trans observations are available.
VCEP rule
Not applicable for this VCEP; BS2 is used instead.
Evidence considered
The governing MSH6 InSiGHT VCEP Version 2.0 framework marks BP2 as not applicable and states: BS2 is used instead.
BP3VCEPNot applicable: designated by the MSH6 VCEP, and the variant is intronic rather than an in-frame protein indel.
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Reasoning
The MSH6 VCEP specification (cspec v2.0) explicitly designates BP3 (in-frame indels in a repetitive region without a known function) as Not Applicable for this gene. This variant is also intronic rather than an in-frame protein indel, so a BP3 repeat-region protein assessment does not apply regardless of the VCEP override.
VCEP rule
MSH6 VCEP cspec v2.0: BP3 applicability = Not Applicable.
Evidence considered
MSH6 VCEP v2.0 lists BP3 with applicability: 'Not Applicable' for this gene.
Variant is a deep-intronic deletion, not an in-frame protein-coding indel, so BP3's repeat-region protein-length criterion is not a relevant assessment regardless of the VCEP applicability flag.
BP6VCEPNot applicable: designated by the MSH6 VCEP, with no expert-panel benign classification on record.
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Reasoning
The applicable InSiGHT/ClinGen MSH6 V2.0 specification explicitly designates BP6 as not applicable. The exact ClinVar record also lacks an expert-panel Benign/Likely benign classification.
VCEP rule
BP6: Not Applicable under the MSH6 V2.0 specification; an exact-variant ClinVar expert-panel Benign/Likely benign classification would be required by the adjudication instructions, and none is present.
Evidence considered
The governing MSH6 V2.0 specification lists BP6 as not applicable.
The exact ClinVar record is a single-submitter Uncertain significance assertion with zero expert-panel submissions, so ordinary or aggregate ClinVar evidence cannot trigger BP6.
AF 4.2e-06 · 6 / 1,444,646 alleles · 0 hom · FAF 5e-06
African/African American2 / 66,074
3e-05
South Asian2 / 80,206
2.5e-05
European (non-Finnish)2 / 1,068,500
1.9e-06
0 alternate alleles recorded in 7 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.15327e-06; MAF= 0.00042%, 6/1444646 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 3.02691e-05; MAF= 0.00303%, 2/66074 alleles, homozygotes = 0); grpmax FAF= 5.02e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Pangolin splice lossmagnitude shown
-0.071
Pangolin splice gain
0.017
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
BP4SupportingMet (Supporting): SpliceAI max delta 0.00, below the <=0.1 no-splice-impact threshold for intronic variants.
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Reasoning
The InSiGHT MMR VCEP (MSH6) BP4 rule states that for intronic and synonymous variants, SpliceAI predicting no splicing impact with delta score <= 0.1 satisfies BP4 at Supporting strength (per Walker et al 2023). NM_000179.3:c.4002-16_4002-10del is an intronic (non-canonical, acceptor-region) deletion. SpliceAI Lookup for this exact variant returned a max delta score of 0.00 (well below the <=0.1 threshold), so BP4_Supporting is met via the splice-impact path of this criterion.
Rule
InSiGHT MMR VCEP (MSH6) cspec v2.0 BP4: SpliceAI delta score <= 0.1 for intronic/synonymous variant (Walker et al 2023) met (score = 0.00) -> BP4_Supporting.
Evidence considered
SpliceAI Lookup for NM_000179.3:c.4002-16_4002-10del: max delta score = 0.00, satisfying the VCEP BP4 splice-impact threshold of <=0.1.
InSiGHT MMR VCEP (MSH6) cspec BP4 rule: 'For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.'
PP3Not met: SpliceAI max delta 0.00 versus the >=0.2 splice-impact threshold.
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Reasoning
NM_000179.3:c.4002-16_4002-10del is a non-canonical intronic deletion (acceptor-region, -16 to -10 relative to the downstream exon). The governing InSiGHT MMR VCEP (MSH6) specification requires, for the splice-impact path of PP3, a predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 (per Walker et al 2023). SpliceAI Lookup for this exact variant returned a max delta score of 0.00 (evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00)'), well below the >=0.2 threshold. The missense HCI-prior path of PP3 does not apply because this variant is not a missense substitution. PP3 is therefore not met.
Rule
InSiGHT MMR VCEP (MSH6) cspec v2.0 PP3: SpliceAI delta score >= 0.2 for non-canonical splice nucleotides (Walker et al 2023) not met (score = 0.00).
Evidence considered
SpliceAI Lookup (spliceailookup.broadinstitute.org) for NM_000179.3:c.4002-16_4002-10del returned max delta score = 0.00, far below the VCEP PP3 splice-impact threshold of >=0.2.
InSiGHT MMR VCEP (MSH6) cspec PP3 rule: 'Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.'
Variant is an intronic deletion, not a missense substitution, so the HCI-prior missense path of PP3 (>0.68 HCI prior) is not applicable.
BP7Not met: the intronic deletion at -16 to -10 lies closer to the exon than the required -21 boundary.
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Reasoning
The InSiGHT MMR VCEP (MSH6) BP7 rule requires a synonymous (silent) or intronic variant at or beyond -21/+7 relative to the exon boundary (5'/3'). This variant, NM_000179.3:c.4002-16_4002-10del, is an intronic deletion spanning positions -16 to -10 relative to the downstream exon (acceptor-region, within the polypyrimidine tract/branch-point zone), which is closer to the exon than the -21 boundary and therefore does not satisfy the 'at or beyond -21/+7' positional requirement. It is also not a synonymous variant. BP7 is therefore not met despite the SpliceAI null-impact result already being captured under BP4.
Rule
InSiGHT MMR VCEP (MSH6) cspec v2.0 BP7: intronic/synonymous variant at or beyond -21/+7 not met (variant at -16 to -10, inside the -21 boundary).
Evidence considered
InSiGHT MMR VCEP (MSH6) cspec BP7 rule: 'A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.'
Variant position (c.4002-16 to c.4002-10) falls within -21 of the exon boundary, not beyond it, so the BP7 positional criterion is not satisfied; variant is not synonymous.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
Karbassi I et al. · 2016
This paper describes a general rules-based variant scoring system using aggregate pathogenicity assessments and evidence categories. Inspection of the available full text found no mention of the exact variant NM_000179.3:c.4002-16_4002-10del and no expert-panel ClinVar classification for it; it therefore provides no PP5 evidence.
In the present study, we describe the application of these recommendations using a standardized, rules‐based process that provides a variant pathogenicity risk score based on clinical grade information in a CLIA‐certified laboratory.
Introduction
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.16 / 1,444,646 recorded allelesOpen source ↗
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= 4.15327e-06; MAF= 0.00042%, 6/1444646 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 3.02691e-05; MAF= 0.00303%, 2/66074 alleles, homozygotes = 0); grpmax FAF= 5.02e-06.
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 (1 clinical laboratory). (ClinVarID = 3572007)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).
This variant was interpreted by pipeline 7.1.0.
The current version is 11.0.07.
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