Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
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 MSH2
MSH2 is a tumor suppressor gene that encodes a key protein in the DNA mismatch repair system, which finds and fixes errors made during DNA replication. The MSH2 protein pairs with MSH6 or MSH3 to form complexes that recognize mismatched base pairs and trigger their repair. Inherited mutations in MSH2 cause Lynch syndrome (hereditary nonpolyposis colorectal cancer), predisposing to colorectal, endometrial, ovarian, and other cancers, and biallelic mutations cause constitutional mismatch repair deficiency. Loss of MSH2 function increases the mutation rate and drives tumor development, particularly in colorectal and endometrial cancers, and mismatch-repair-deficient tumors respond particularly well to immune checkpoint inhibitor therapies.
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01The reasoning
How it was classified
The recorded framework is ClinGen MSH2 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 MSH2 VCEP v2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 2 not met · 9 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
MSH2 has a VCEP-specific (ClinGen InSiGHT) CSPEC v2.0 that governs PVS1, PM4, and BP3 for this gene; it was used in preference to generic ACMG/AMP guidance.
c.712del (NP_000242.1:p.(Tyr238IlefsTer8)) is a frameshift in exon 4 introducing a PTC at ~codon 245, well below the MSH2 VCEP's codon-891 Very Strong PVS1 threshold, so PVS1 is met at Very Strong.
PM4 and BP3 are both explicitly designated Not Applicable for MSH2 by the VCEP framework, and neither criterion's underlying mechanism (in-frame protein length change) applies to this frameshift variant in any case.
NM_000251.3:c.712del produces a frameshift (NP_000242.1:p.(Tyr238IlefsTer8)), not a missense substitution.
All five criteria in this group (PS1, PM1, PM5, PP2, BP1) are missense/residue-comparison codes; PM1, PP2, and BP1 are additionally explicitly marked 'Not Applicable' for MSH2 by the InSiGHT MMR VCEP CSPEC v2.0.
PS1 and PM5 are structurally inapplicable because both require the variant under review to be a missense substitution being compared at the amino-acid level to another missense variant; a frameshift deletion has no such comparison basis.
PS3 and BS3 both require calibrated, variant-specific MMR functional assay data (protein-, mRNA-, or monoallelic-expression-based) per the InSiGHT MMR VCEP specification (cspec v2.0). No such variant-specific data for NM_000251.3:c.712del was located in the prefetch, evidence, literature_pass, vcep_materials, or fulltext_map sections of the case-evidence bundle, so both criteria are returned as not_assessed rather than met or not_met.
NM_000251.3:c.712del is a single-nucleotide coding deletion producing a frameshift, p.(Tyr238IlefsTer8), located 66 nt into exon 4, not at a splice consensus site and not a missense or synonymous substitution.
The InSiGHT MSH2 VCEP (cspec v2.0) scopes PP3/BP4 to two calibrated sub-paths only: missense variants via the HCI-prior lookup, and intronic/synonymous or non-canonical-splice-nucleotide variants via SpliceAI. BP7 is scoped to synonymous/deep-intronic variants only.
This frameshift deletion falls into none of those variant-type gates: prefetch.json explicitly skipped HCI-prior ('not_substitution_or_missing_coding_hgvs'), REVEL and BayesDel ('not snv or no coords'), confirming no calibrated missense computational-evidence code applies.
SpliceAI was still run for completeness and returned a negligible max delta score (0.024), consistent with no splicing disruption, but since the variant is not intronic/synonymous the VCEP's BP4 splice sub-path does not formally apply; the score is reported in evidence_used for audit purposes only, not used to call BP4 met.
All three criteria (PP3, BP4, BP7) are therefore not_applicable for this frameshift deletion; the variant's predicted loss-of-function impact belongs to the PVS1 domain, evaluated by a different criteria group.
Population evidence supports PM2 at Supporting strength only; BA1 and BS1 frequency thresholds are not met, and BS2 is not assessable from the available case evidence.
No criteria match.
Met · 2
PVS1Very strongMet (Very Strong): frameshift introduces a premature stop at codon 245, before the VCEP threshold of codon 891, predicting nonsense-mediated decay.
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Reasoning
NM_000251.3:c.712del is a single-nucleotide deletion in exon 4 of MSH2 (VariantValidator: start_exon=end_exon=4 on both GRCh37/38) predicted to cause a frameshift, NP_000242.1:p.(Tyr238IlefsTer8), introducing a premature termination codon at approximately codon 245 of the 934-aa MSH2 protein. The InSiGHT MMR VCEP (ClinGen CSPEC v2.0) PVS1 rule for MSH2 assigns Pathogenic Very Strong to any nonsense/frameshift variant introducing a PTC at or before codon 891; codon 245 is well within this range. The MSH2 gene-level PVS1 gate is eligible (germline LOF is an established MSH2 disease mechanism per the VCEP framework itself), and this variant is not an initiation-codon variant (the VCEP's sole stated PVS1 exception for MSH2), so no exception applies. A PTC this early (exon 4 of a 16-exon transcript) removes the majority of the protein including all downstream functional domains, consistent with nonsense-mediated decay and/or a severely truncated non-functional product; this is captured directly by the codon-based VCEP threshold rather than requiring a separate NMD calculation.
Rule
InSiGHT MMR VCEP CSPEC v2.0 PVS1: PTC <= codon 891 in MSH2 -> Pathogenic Very Strong
Evidence considered
VariantValidator normalization places c.712del in exon 4 (start_exon=end_exon=4) with protein consequence NP_000242.1:p.(Tyr238IlefsTer8), a frameshift introducing a premature stop 8 codons after residue 238 (~codon 245).
InSiGHT MMR VCEP CSPEC v2.0 PVS1 rule (Pathogenic Very Strong): 'Nonsense/frameshift variant introducing Premature Termination Codon (PTC) <= codon 891 in MSH2.' Codon 245 falls well within this range.
pvs1_gene_context.json confirms the MSH2 PVS1 gene gate is 'eligible' because the CSPEC/VCEP explicitly includes PVS1 guidance for MSH2, establishing germline loss of function as the disease mechanism.
The VCEP's only stated PVS1 non-applicability exception for MSH2 is initiation-codon variants (alternate in-frame ATG in exon 1); this variant is a frameshift in exon 4, so the exception does not apply.
PM2SupportingMet (Supporting): absent from gnomAD v4.1, below the 1-in-50,000 allele-frequency threshold.
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Reasoning
PM2_Supporting is met: the variant is absent from gnomAD v4.1, satisfying the InSiGHT MSH2 requirement for an allele frequency <0.00002 (<1 in 50,000 alleles).
Rule
InSiGHT MSH2 VCEP PM2_Supporting: absent or extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4.
Evidence considered
gnomAD v4.1 direct-variant query for GRCh38 chr2-47412477-AT-A reported the variant as absent, which is below 0.00002.
The InSiGHT MSH2 VCEP PM2 rule assigns Supporting strength for an absent or extremely rare gnomAD v4 allele frequency <0.00002 (<1 in 50,000 alleles).
BA1Not met: absent from gnomAD v4.1, far below the >=0.001 population frequency threshold.
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Reasoning
BA1 is not met: the variant is absent from gnomAD v4.1, so it does not reach the InSiGHT MSH2 BA1 Grpmax filtering allele-frequency threshold of ≥0.001.
Rule
InSiGHT MSH2 VCEP BA1: gnomAD v4 Grpmax filtering allele frequency ≥0.001 (0.1%) and variant excluded as a founder pathogenic variant.
Evidence considered
gnomAD v4.1 direct-variant query for GRCh38 chr2-47412477-AT-A reported the variant as absent; therefore no Grpmax filtering allele frequency can meet the BA1 threshold.
The InSiGHT MSH2 VCEP BA1 rule requires a gnomAD v4 Grpmax filtering allele frequency ≥0.001 (0.1%) and exclusion as a founder pathogenic variant.
BS1Not met: absent from gnomAD v4.1, below the 0.0001-0.001 population frequency interval.
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Reasoning
BS1 is not met: the variant is absent from gnomAD v4.1, so it does not reach the InSiGHT MSH2 BS1 Grpmax filtering allele-frequency interval of ≥0.0001 and <0.001.
Rule
InSiGHT MSH2 VCEP BS1: gnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001 (0.01–0.1%) and variant excluded as a founder pathogenic variant.
Evidence considered
gnomAD v4.1 direct-variant query for GRCh38 chr2-47412477-AT-A reported the variant as absent; therefore no Grpmax filtering allele frequency can fall within the BS1 interval.
The InSiGHT MSH2 VCEP BS1 rule requires a gnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001 (0.01–0.1%) and exclusion as a founder pathogenic variant.
PS2Not assessed: no de novo observation with parental testing or phenotype information was available.
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Reasoning
No proband-level de novo observation, parental test results, parentage confirmation, phenotype information, or de novo point total is present in the case-evidence bundle.
Rule
MSH2 InSiGHT VCEP v2.0 PS2: >=4 de novo points (Very Strong); 2–3.5 (Strong); 1–1.5 (Moderate); 0.5 (Supporting).
Evidence considered
The MSH2 InSiGHT VCEP specification applies PS2 by accumulated de novo points: supporting at 0.5, moderate at 1–1.5, strong at 2–3.5, and very strong at at least 4 points. The bundle contains no de novo case or parental-testing evidence from which to assign points.
Still missing
Variant test results for both biological parents.
Confirmation of biological parentage and germline origin.
Proband phenotype and age at diagnosis sufficient to assign MSH2 de novo points under the InSiGHT specification.
PS3Not assessed: no variant-specific functional assay result (e.g., MMR activity or mRNA stability) was available.
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Reasoning
The InSiGHT MMR VCEP specification (cspec v2.0) calibrates PS3 for MSH2 using functional odds for pathogenicity from validated MMR functional assays (protein/mRNA-based assays per the flowchart, or monoallelic expression/NMD-block cDNA assays), with tiers at >18.7 (Strong), >4.3-<=18.7 (Moderate), and >2.08-<=4.3 (Supporting). No variant-specific functional assay data (e.g. yeast/human cell MMR activity assay, mRNA stability, monoallelic expression cDNA assay) for NM_000251.3:c.712del (p.Tyr238Ilefs*8) is present anywhere in the case-evidence bundle (prefetch, evidence, literature_pass, vcep_materials, fulltext_map). The OncoKB entry reports a curated 'Likely Loss-of-function'/'Likely Oncogenic' annotation, but this is a database-level literature/computational summary, not a calibrated functional assay readout with an odds-of-pathogenicity value, so it cannot be used to satisfy PS3. This is a frameshift/premature-termination variant (c.712del) predicted to undergo NMD and is evaluated primarily under PVS1 in this framework; no monoallelic-expression or NMD-block cDNA assay results specific to this variant were retrieved.
Evidence considered
OncoKB (evidence.json) reports biological_effect 'Likely Loss-of-function' and classification 'Likely Oncogenic' for MSH2 Y238Ifs*8, but this is a curated database annotation, not a calibrated functional assay odds-of-pathogenicity value, so it does not meet the VCEP PS3 evidentiary bar.
No PMID in source_registry.json or literature_pass.json describes a variant-specific MMR functional (complementation, MMR activity, or mRNA/protein) assay for c.712del; the high-priority OncoKB-derived PMIDs (10946232, 11257106, 15528792, 23391514, 24362816) are general MMR structure/function or database-classification reviews, not variant-specific assay reports.
Still missing
No calibrated MMR functional assay (protein or mRNA-based) result specific to c.712del/p.Tyr238Ilefs*8 was found in prefetch/evidence/literature_pass sources.
No monoallelic expression or NMD-block cDNA assay data for this variant was retrieved.
The Functional-assay-SVI-documentation-MMR.xlsx and Functional-assay-flowchart.pdf VCEP materials were listed as applicable to PS3/BS3 but no extracted content (parsed table rows or variant-specific assay hits) for this variant was present in vcep_materials.json.
PM3Not assessed: no observation of the variant with a second MSH2 variant or phase testing was available.
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Reasoning
The applicable InSiGHT MSH2 VCEP specification permits PM3 only from scored biallelic observations (0.5, 1–1.5, 2–3.5, or ≥4 points). The case bundle contains no affected-proband observation of NM_000251.3:c.712del with a second MSH2 variant, no pathogenic/likely pathogenic partner variant, and no phase or parental/offspring testing. Therefore no PM3 points can be assigned.
The case bundle reports MSH2-associated autosomal dominant Lynch syndrome 1 and autosomal recessive mismatch repair cancer syndrome 1, but provides no individual-level biallelic observation for this variant.
Still missing
Affected-proband-level evidence of a second MSH2 variant is required.
Phase evidence establishing trans configuration (preferably parental or offspring testing) and the clinical phenotype/CMMRD status of the biallelic individual are required to score PM3.
PP1Not assessed: no pedigree or relative genotype data was available for co-segregation analysis.
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Reasoning
No pedigree, relative genotypes, disease statuses, ages, or combined Bayes likelihood ratio is present in the case-evidence bundle, so co-segregation cannot be evaluated.
Rule
MSH2 InSiGHT VCEP v2.0 PP1: combined Bayes likelihood ratio >2.08–4.3 (Supporting), >4.3–18.7 (Moderate), or >18.7 in >=2 families (Strong).
Evidence considered
The MSH2 InSiGHT VCEP specification requires a combined pedigree Bayes likelihood ratio greater than 2.08 to apply PP1 at supporting strength, greater than 4.3 for moderate, and greater than 18.7 in at least two families for strong. No segregation data or likelihood ratio is supplied.
Still missing
Pedigree with tested relatives, relationship structure, cancer diagnoses, and ages at diagnosis or current ages.
Variant genotypes for informative relatives.
Combined Bayes likelihood ratio calculated using the VCEP-recommended segregation analysis approach.
PP4Not assessed: no tumor MSI or MMR immunohistochemistry result was provided.
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Reasoning
No case-level CRC/endometrial tumor MSI result or MMR IHC result is provided, so the VCEP PP4 tumor threshold cannot be evaluated.
Rule
InSiGHT MSH2 VCEP PP4: 1/2/at least 3 independent CRC or endometrial MSI-H tumors and/or MMR IHC loss consistent with MSH2 support Supporting/Moderate/Strong evidence, respectively.
Evidence considered
The MSH2 VCEP applies PP4 at Supporting for one, Moderate for two, and Strong for at least three independent CRC/endometrial MSI-H tumors and/or MMR protein-expression loss consistent with an MSH2 variant; no such case-level tumor observations are present in the evidence bundle.
Still missing
Obtain tumor-specific MSI testing and/or MMR IHC results, with tumor type and independent-tumor count, to assess the VCEP PP4 threshold.
BS2Not assessed: no evidence of the variant in trans with a known pathogenic MSH2 variant was available.
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Reasoning
BS2 cannot be assessed because no case-level evidence documents the variant in trans with a known pathogenic MSH2 variant, confirmed phase by parental or offspring testing, an eligible later-onset Lynch-spectrum cancer, and absence of CMMRD manifestations.
Rule
InSiGHT MSH2 VCEP BS2: co-occurrence in trans with a known pathogenic MSH2 variant in an eligible later-onset Lynch-spectrum cancer case without CMMRD; parental or offspring testing must confirm phase.
Evidence considered
The InSiGHT MSH2 VCEP specifies BS2 only for a variant observed in trans with a known pathogenic sequence variant in MSH2 in an eligible patient, with phase confirmed through testing of parents or offspring and no current or prior CMMRD manifestations. The case bundle provides none of these observations.
Still missing
Case-level genotype, phase confirmation, age and cancer diagnosis, and CMMRD clinical assessment are required by the MSH2 VCEP BS2 rule.
BS3Not assessed: no calibrated functional assay result showing proficient MSH2 function was available.
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Reasoning
The InSiGHT MMR VCEP specification calibrates BS3 for MSH2 using calibrated functional assays with functional odds for pathogenicity <=0.05 (Strong) or >0.05-<=0.48 (Supporting), or (for synonymous/intronic variants only) absence of mRNA aberration under NMD-inhibited assay conditions. c.712del is a single-base coding deletion causing a frameshift (p.Tyr238Ilefs*8), not a synonymous or intronic variant, so the mRNA-aberration-absence pathway is not applicable to it. No calibrated functional assay data of any kind (protein or mRNA-based) for this specific variant was found anywhere in the case-evidence bundle to support a benign/proficient-function readout.
Still missing
No calibrated MMR functional assay result for c.712del was found showing proficient (wild-type-like) function.
Variant is a frameshift/PTC-introducing deletion, so the BS3 mRNA-aberration-absence pathway (reserved for synonymous/intronic variants) is not applicable.
BS4Not assessed: no informative non-segregation or pedigree observations were available.
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Reasoning
No informative non-segregation observations or combined Bayes likelihood ratio is present in the case-evidence bundle; BS4 cannot be evaluated.
Rule
MSH2 InSiGHT VCEP v2.0 BS4: combined Bayes likelihood ratio <0.05 (Strong) or >0.05 and <=0.48 (Supporting).
Evidence considered
The MSH2 InSiGHT VCEP specification assigns BS4 only when the combined pedigree Bayes likelihood ratio is below 0.05 (strong) or greater than 0.05 through 0.48 (supporting). No such calculation or underlying pedigree data is supplied.
Still missing
Pedigree with disease status, age information, and variant genotypes for informative relatives.
Assessment of phenocopies and other familial causes of cancer.
Combined Bayes likelihood ratio calculated using the VCEP-recommended segregation analysis approach.
BP5Not assessed: no tumor MSS, IHC, BRAF V600E, or MLH1 methylation evidence was provided.
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Reasoning
No tumor-level MSS, retained/discordant MMR IHC, BRAF V600E, or MLH1 methylation evidence is provided; BP5 cannot be evaluated.
Rule
InSiGHT MSH2 VCEP BP5: Supporting for 2-3 qualifying tumors or 1 qualifying BRAF V600E/MLH1-methylated tumor; Strong for at least 4 qualifying tumors or at least 2 qualifying BRAF V600E/MLH1-methylated tumors.
Evidence considered
The MSH2 VCEP permits BP5_Supporting for two or three qualifying tumors with MSS, no MMR protein loss, or MMR loss inconsistent with MSH2, or for one qualifying BRAF V600E or MLH1-methylated tumor; it permits BP5_Strong at four or more qualifying tumors or at least two qualifying BRAF V600E/MLH1-methylated tumors. No such data are in the evidence bundle.
Still missing
Obtain tumor MSI and MMR IHC results and, where relevant, BRAF V600E and MLH1 promoter methylation testing, including the number of independent tumors.
Not applicable · 15· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: this is a frameshift deletion, not a missense or splice-site change, so the same-amino-acid comparison cannot apply.
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Reasoning
PS1 per the InSiGHT MMR VCEP (MSH2 CSPEC v2.0) requires a predicted missense substitution encoding the SAME amino acid change as a different nucleotide change previously established Pathogenic by the VCEP, or a non-canonical splice-site nucleotide match. NM_000251.3:c.712del is a single-base deletion causing a frameshift (NP_000242.1:p.(Tyr238IlefsTer8)), not a missense substitution and not a splice-site variant. The rule's structural premise (same amino acid substitution via alternate codon) cannot apply to a frameshift.
Rule
InSiGHT MMR VCEP MSH2 CSPEC v2.0 PS1
Evidence considered
VCEP CSPEC PS1 rule requires a predicted missense substitution encoding the same amino acid change via a different nucleotide change (or a matching non-canonical splice-site nucleotide); the variant under review is a frameshift deletion (p.Tyr238IlefsTer8), so PS1's structural premise does not apply.
PS4VCEPNot applicable: tumor IHC evidence is evaluated through PP4 under this gene's framework, not proband counting.
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Reasoning
PS4 is not used for MSH2 under the applicable InSiGHT VCEP specification because tumor IHC evidence is evaluated through PP4 rather than proband counting.
VCEP rule
InSiGHT MSH2 VCEP: PS4 not applicable; tumor IHC evidence is assessed under PP4 rather than through proband counting.
Evidence considered
The MSH2 InSiGHT VCEP specification states that PS4 is not applicable because tumor IHC data are available for variant classification through PP4.
PM1VCEPNot applicable: this gene's expert framework designates PM1 as not applicable for MSH2.
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Reasoning
The MSH2 CSPEC (InSiGHT MMR VCEP v2.0) explicitly designates PM1 as Not Applicable for this gene. No gene-specific PM1 rule exists to apply, and generic ACMG PM1 (mutational hotspot/functional domain) is superseded by the VCEP designation per framework precedence.
VCEP rule
InSiGHT MMR VCEP MSH2 CSPEC v2.0 PM1 = Not Applicable
Evidence considered
MSH2 CSPEC v2.0 lists PM1 with applicability: 'Not Applicable', overriding generic ACMG PM1 for this gene.
PM4VCEPNot applicable: already fully scored under PVS1 as a truncating frameshift, not an in-frame length change.
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Reasoning
The InSiGHT MMR VCEP CSPEC v2.0 explicitly marks PM4 as Not Applicable for MSH2. This is also consistent with the generic ACMG/AMP framework: PM4 (protein length change via in-frame indel or stop-loss) is intended for variants not already captured by PVS1, and this variant is a frameshift that has already been fully scored under PVS1 (Very Strong) as a canonical null/loss-of-function variant, not an in-frame length change.
VCEP rule
InSiGHT MMR VCEP CSPEC v2.0 PM4: Not Applicable for MSH2
Evidence considered
InSiGHT MMR VCEP CSPEC v2.0 lists PM4 with applicability: 'Not Applicable' for MSH2.
c.712del produces a frameshift (NP_000242.1:p.(Tyr238IlefsTer8)), not an in-frame insertion/deletion or stop-loss event, so the generic PM4 mechanism (protein length change) does not apply; the loss-of-function consequence is already fully captured by PVS1.
PM5N/ANot applicable: this is a frameshift deletion, not a missense change, so residue-level missense comparison does not apply.
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Reasoning
PM5 per the MSH2 CSPEC applies to a missense change at a residue where a DIFFERENT missense change was classified Pathogenic/Likely Pathogenic by the VCEP (protein-level effect, not aberrant splicing), and additionally requires PP3 to be supporting for the new missense change. NM_000251.3:c.712del is a frameshift deletion, not a missense substitution, so the residue-level missense comparison this rule is built around cannot be performed.
Rule
InSiGHT MMR VCEP MSH2 CSPEC v2.0 PM5
Evidence considered
VCEP CSPEC PM5 rule is restricted to 'missense change at an amino acid residue where a different missense change was classified... as Pathogenic/Likely Pathogenic on the protein level'; the variant under review is a frameshift, not a missense substitution, so PM5 cannot be evaluated.
PM6VCEPNot applicable: unconfirmed de novo observations are not evaluated for this gene under its expert framework.
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Reasoning
PM6 is designated not applicable by the MSH2 InSiGHT VCEP specification; unconfirmed de novo observations are therefore not evaluated under PM6 for this gene-specific framework.
VCEP rule
MSH2 InSiGHT VCEP v2.0: PM6 not applicable.
Evidence considered
The applicable MSH2 InSiGHT VCEP v2.0 framework explicitly marks PM6 as not applicable.
PP2VCEPNot applicable: this gene's expert framework excludes PP2, and the variant is a frameshift, not missense.
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Reasoning
The MSH2 CSPEC (InSiGHT MMR VCEP v2.0) explicitly designates PP2 as Not Applicable for this gene. PP2 (missense in a gene with low benign missense rate) is also structurally inapplicable to this frameshift variant regardless.
VCEP rule
InSiGHT MMR VCEP MSH2 CSPEC v2.0 PP2 = Not Applicable
Evidence considered
MSH2 CSPEC v2.0 lists PP2 with applicability: 'Not Applicable'.
Variant is a frameshift deletion, not a missense variant, so PP2's missense-gene-mechanism premise does not apply independent of the VCEP designation.
PP3N/ANot applicable: PP3 covers missense or splice-site variants; this frameshift's impact is assessed under PVS1.
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Reasoning
NM_000251.3:c.712del is a single-nucleotide frameshift deletion (p.(Tyr238IlefsTer8)) located well within exon 4 (exon 4 spans c.646-792 per Mutalyzer transcript model), not a missense substitution and not within -21/+7 of a splice junction. The InSiGHT MSH2 VCEP (cspec v2.0) restricts PP3 to (a) missense variants scored by the HCI-prior tool, or (b) variants affecting a non-canonical splice nucleotide scored by SpliceAI. This frameshift deletion satisfies neither sub-path: HCI-prior lookup was explicitly skipped as not applicable ('not_substitution_or_missing_coding_hgvs'), and the deletion is not adjacent to a splice consensus sequence. PP3 is therefore not applicable to this variant type; its predicted impact (nonsense-mediated decay / truncation) is properly assessed under PVS1, not the calibrated in-silico path.
Rule
InSiGHT MSH2 VCEP cspec v2.0 PP3: restricted to missense (HCI-prior) or non-canonical splice-nucleotide (SpliceAI) variants; frameshift deletions are out of scope and evaluated under PVS1 instead.
Evidence considered
Mutalyzer normalized model places c.712del within exon 4 (c.646-792), 66 nt from the nearest exon boundary, i.e. not a canonical/non-canonical splice-site nucleotide.
prefetch.json hci_prior step: found=false, reason='not_substitution_or_missing_coding_hgvs' -- HCI-prior lookup does not apply to this indel.
InSiGHT MSH2 cspec v2.0 PP3 rule is scoped to missense HCI-prior >0.68 or SpliceAI-scored non-canonical splice nucleotide substitutions; neither sub-path covers an exonic frameshift deletion.
PP5VCEPNot applicable: no expert-panel assertion exists in ClinVar for this exact variant.
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Reasoning
PP5 is not applicable in the MSH2 VCEP specification. ClinVar contains only two exact-variant single-submitter laboratory assertions and no expert-panel submission; therefore no expert-panel PP5 assertion is available.
VCEP rule
InSiGHT MSH2 VCEP: PP5 not applicable. Per this review, only an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic assertion could otherwise qualify for PP5.
Evidence considered
The MSH2 InSiGHT VCEP marks PP5 not applicable, following the ClinGen SVI VCEP Review Committee recommendation.
ClinVar variation 1757305 exactly matches NM_000251.3:c.712del, but its two Pathogenic submissions are from Myriad Genetics and Ambry Genetics, both single submitters rather than an expert panel; their classifications were not used as evidence for PP5.
BP1VCEPNot applicable: this gene's framework excludes BP1, and the variant is truncating, not missense.
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Reasoning
The MSH2 CSPEC (InSiGHT MMR VCEP v2.0) explicitly designates BP1 as Not Applicable for this gene. BP1 (missense variant in a gene where only truncating variants cause disease) is also structurally inapplicable here since the variant is a truncating frameshift, not a missense change.
VCEP rule
InSiGHT MMR VCEP MSH2 CSPEC v2.0 BP1 = Not Applicable
Evidence considered
MSH2 CSPEC v2.0 lists BP1 with applicability: 'Not Applicable'.
BP1 evaluates missense variants in genes where disease is caused only by truncating variants; this variant is itself a truncating frameshift, not a missense variant.
BP2 is explicitly designated Not Applicable by the governing InSiGHT MSH2 VCEP specification. No generic ACMG/AMP fallback is used because an applicable gene-specific specification exists.
VCEP rule
InSiGHT MSH2 VCEP: BP2 Not Applicable.
Evidence considered
The InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel MSH2 v2.0 specification lists BP2 as Not Applicable.
BP3VCEPNot applicable: BP3 covers in-frame indels; this is a frameshift deletion.
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Reasoning
The InSiGHT MMR VCEP CSPEC v2.0 explicitly marks BP3 as Not Applicable for MSH2. This is also consistent with the generic ACMG/AMP framework: BP3 applies to in-frame indels in a repetitive region without a known function, and this variant is a frameshift (not an in-frame indel), so the BP3 mechanism does not apply regardless of the VCEP's blanket exclusion.
VCEP rule
InSiGHT MMR VCEP CSPEC v2.0 BP3: Not Applicable for MSH2
Evidence considered
InSiGHT MMR VCEP CSPEC v2.0 lists BP3 with applicability: 'Not Applicable' for MSH2.
c.712del is a frameshift deletion, not an in-frame indel in a repetitive/non-functional region, so BP3's underlying mechanism is not met independent of the VCEP's exclusion.
BP4N/ANot applicable: BP4 covers only missense or intronic/synonymous variants; this is a frameshift deletion.
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Reasoning
The InSiGHT MSH2 VCEP BP4 rule applies only to (a) missense variants via HCI-prior <0.11, or (b) intronic/synonymous variants via SpliceAI delta score <=0.1 (Walker et al 2023). c.712del is a frameshift deletion, neither missense nor intronic/synonymous, so BP4 does not apply regardless of the SpliceAI result. For completeness, SpliceAI Lookup (screenshot, evidence.json) reported a negligible max delta score of 0.024 (DS_AG 0.024, DS_AL 0.001, DS_DG 0.002, DS_DL 0.0), which would be below the BP4 splicing threshold if the variant type qualified, but the VCEP-defined variant-type gate is not met so the criterion is not_applicable rather than met.
Rule
InSiGHT MSH2 VCEP cspec v2.0 BP4: missense HCI-prior <0.11, or SpliceAI <=0.1 for intronic/synonymous variants only; frameshift deletions are excluded from this criterion's scope.
Evidence considered
SpliceAI Lookup result (evidence.json): max_delta_score = 0.024 (DS_AG 0.024, DS_AL 0.001, DS_DG 0.002, DS_DL 0.0), well below any splicing-impact threshold, but reported only for context since variant type is not intronic/synonymous.
InSiGHT MSH2 cspec v2.0 BP4 rule text: 'Missense variant with HCI-prior probability of pathogenicity <0.11 ... OR For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <=0.1 as per Walker et al 2023.' -- c.712del is neither missense nor intronic/synonymous.
prefetch.json bayesdel/revel steps both skipped with reason 'not snv or no coords', confirming no calibrated missense computational score is available or applicable to this indel.
BP6VCEPNot applicable: no expert-panel benign assertion exists in ClinVar for this exact variant.
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Reasoning
BP6 is not applicable in the MSH2 VCEP specification, and ClinVar has no exact-variant expert-panel benign or likely benign assertion.
VCEP rule
InSiGHT MSH2 VCEP: BP6 not applicable. Per this review, only an exact-variant ClinVar expert-panel Benign/Likely benign assertion could otherwise qualify for BP6.
Evidence considered
The MSH2 InSiGHT VCEP marks BP6 not applicable, following the ClinGen SVI VCEP Review Committee recommendation.
ClinVar variation 1757305 exactly matches NM_000251.3:c.712del but has no expert-panel submissions and no benign or likely benign assertion; ordinary laboratory submissions cannot trigger BP6.
BP7N/ANot applicable: BP7 covers only synonymous or intronic variants; this is a coding frameshift deletion.
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Reasoning
BP7 under the InSiGHT MSH2 VCEP specification applies only to a synonymous (silent) or intronic variant at or beyond -21/+7 of the splice junction. NM_000251.3:c.712del is a coding frameshift deletion causing p.(Tyr238IlefsTer8), not a synonymous or intronic change, so BP7 cannot apply.
Rule
InSiGHT MSH2 VCEP cspec v2.0 BP7: synonymous or deep intronic (-21/+7) variants only; not applicable to frameshift deletions.
Evidence considered
Mutalyzer protein prediction (prefetch.json): NM_000251.3:c.712del -> NP_000242.1:p.(Tyr238IlefsTer8), a frameshift/truncating change, not a synonymous substitution.
InSiGHT MSH2 cspec v2.0 BP7 rule: 'A synonymous (silent) or intronic variant at or beyond -21/+7 (5' or 3' exonic).' -- variant type criterion not met.
Every interpreted variant in MSH2, mapped onto the exon structure of NM_000251.3. Select a row to find it on the plot.
MSH2NM_000251.3
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 MSH2—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -63 bp
0.001
SpliceAI acceptor gainat -90 bp
0.024
SpliceAI donor lossat +83 bp
0.000
SpliceAI donor gainat +370 bp
0.002
Pangolin splice lossmagnitude shown
-0.053
Pangolin splice gain
0.008
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: PP3 covers missense or splice-site variants; this frameshift's impact is assessed under PVS1.
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Reasoning
NM_000251.3:c.712del is a single-nucleotide frameshift deletion (p.(Tyr238IlefsTer8)) located well within exon 4 (exon 4 spans c.646-792 per Mutalyzer transcript model), not a missense substitution and not within -21/+7 of a splice junction. The InSiGHT MSH2 VCEP (cspec v2.0) restricts PP3 to (a) missense variants scored by the HCI-prior tool, or (b) variants affecting a non-canonical splice nucleotide scored by SpliceAI. This frameshift deletion satisfies neither sub-path: HCI-prior lookup was explicitly skipped as not applicable ('not_substitution_or_missing_coding_hgvs'), and the deletion is not adjacent to a splice consensus sequence. PP3 is therefore not applicable to this variant type; its predicted impact (nonsense-mediated decay / truncation) is properly assessed under PVS1, not the calibrated in-silico path.
Rule
InSiGHT MSH2 VCEP cspec v2.0 PP3: restricted to missense (HCI-prior) or non-canonical splice-nucleotide (SpliceAI) variants; frameshift deletions are out of scope and evaluated under PVS1 instead.
Evidence considered
Mutalyzer normalized model places c.712del within exon 4 (c.646-792), 66 nt from the nearest exon boundary, i.e. not a canonical/non-canonical splice-site nucleotide.
prefetch.json hci_prior step: found=false, reason='not_substitution_or_missing_coding_hgvs' -- HCI-prior lookup does not apply to this indel.
InSiGHT MSH2 cspec v2.0 PP3 rule is scoped to missense HCI-prior >0.68 or SpliceAI-scored non-canonical splice nucleotide substitutions; neither sub-path covers an exonic frameshift deletion.
BP4N/ANot applicable: BP4 covers only missense or intronic/synonymous variants; this is a frameshift deletion.
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Reasoning
The InSiGHT MSH2 VCEP BP4 rule applies only to (a) missense variants via HCI-prior <0.11, or (b) intronic/synonymous variants via SpliceAI delta score <=0.1 (Walker et al 2023). c.712del is a frameshift deletion, neither missense nor intronic/synonymous, so BP4 does not apply regardless of the SpliceAI result. For completeness, SpliceAI Lookup (screenshot, evidence.json) reported a negligible max delta score of 0.024 (DS_AG 0.024, DS_AL 0.001, DS_DG 0.002, DS_DL 0.0), which would be below the BP4 splicing threshold if the variant type qualified, but the VCEP-defined variant-type gate is not met so the criterion is not_applicable rather than met.
Rule
InSiGHT MSH2 VCEP cspec v2.0 BP4: missense HCI-prior <0.11, or SpliceAI <=0.1 for intronic/synonymous variants only; frameshift deletions are excluded from this criterion's scope.
Evidence considered
SpliceAI Lookup result (evidence.json): max_delta_score = 0.024 (DS_AG 0.024, DS_AL 0.001, DS_DG 0.002, DS_DL 0.0), well below any splicing-impact threshold, but reported only for context since variant type is not intronic/synonymous.
InSiGHT MSH2 cspec v2.0 BP4 rule text: 'Missense variant with HCI-prior probability of pathogenicity <0.11 ... OR For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <=0.1 as per Walker et al 2023.' -- c.712del is neither missense nor intronic/synonymous.
prefetch.json bayesdel/revel steps both skipped with reason 'not snv or no coords', confirming no calibrated missense computational score is available or applicable to this indel.
BP7N/ANot applicable: BP7 covers only synonymous or intronic variants; this is a coding frameshift deletion.
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Reasoning
BP7 under the InSiGHT MSH2 VCEP specification applies only to a synonymous (silent) or intronic variant at or beyond -21/+7 of the splice junction. NM_000251.3:c.712del is a coding frameshift deletion causing p.(Tyr238IlefsTer8), not a synonymous or intronic change, so BP7 cannot apply.
Rule
InSiGHT MSH2 VCEP cspec v2.0 BP7: synonymous or deep intronic (-21/+7) variants only; not applicable to frameshift deletions.
Evidence considered
Mutalyzer protein prediction (prefetch.json): NM_000251.3:c.712del -> NP_000242.1:p.(Tyr238IlefsTer8), a frameshift/truncating change, not a synonymous substitution.
InSiGHT MSH2 cspec v2.0 BP7 rule: 'A synonymous (silent) or intronic variant at or beyond -21/+7 (5' or 3' exonic).' -- variant type criterion not met.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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
Structure and function of mismatch repair proteins.
This variant was interpreted by pipeline 7.1.5.
The current version is 11.0.07.
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