The MSH6 NM_000179.3:c.3261dup (NP_000170.1:p.(Phe1088LeufsTer5)) frameshift variant has previously been reported in somatic cancers (COSMIC; COSV52273592, n = 125 times). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS). This variant is considered to be Pathogenic by the VCEP (International Society for Gastrointestinal Hereditary Tumours (InSiGHT); ClinVar ID 89364).
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 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.
Met, very strong: the frameshift creates a premature stop at approximately codon 1092, below the MSH6 VCEP cutoff of codon 1341.
PP5Supporting
PP5 · supporting
Not applicable: the MSH6 VCEP explicitly prohibits PP5, regardless of pathogenic classifications reported by ClinVar or publications.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
VUS: PVS1 (very strong) plus PP5 (supporting) do not satisfy any ClinGen InSiGHT MSH6 VCEP pathogenic or benign combination rule.
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
91 / 1,610,042 alleles
gnomAD v4.1: 91 / 1,610,042 alleles. Recorded AF 5.65203e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.05249e-05; MAF= 0.00605%, 17/280876 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000278629; MAF= 0.02786%, 2/7178 alleles, homozygotes = 0); grpmax FAF= 3.449e-05.
ACMG/AMP criteria under ClinGen MSH6 VCEP v2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 8 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 met at very strong strength under the MSH6 VCEP rule for a frameshift PTC at or before codon 1341; PM4 and BP3 are explicitly not applicable under the same VCEP specification.
All five requested codon/residue/domain criteria are not applicable under the governing MSH6 VCEP specification: the variant is a frameshift, and the VCEP explicitly marks PM1, PP2, and BP1 not applicable while PS1 and PM5 are missense-focused rules.
The requested VCEP fulltext file MMR-Functional-domains.pdf.txt was searched for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5; no exact-variant entry was found.
Only PS2, PM6, PP1, and BS4 were adjudicated under the ClinGen InSiGHT MSH6 Version 2.0 specification. The available evidence documents an affected proband but does not provide parental testing, de novo points, pedigree segregation, non-segregation, or Bayes Likelihood Ratios sufficient to assess PS2, PP1, or BS4; PM6 is explicitly not applicable.
The governing MSH6 VCEP specification was applied exclusively; PS4, PP5, and BP6 are not applicable under the VCEP rules.
PP4 was not met because the exact-variant tumor report documented instability in 2 of 5 markers without a qualifying MSI-H or MSH6-consistent IHC result.
BP5 was not assessed because the available tumor evidence did not establish MSS, qualifying inconsistent MMR loss, BRAF V600E, or MLH1 methylation.
The governing ClinGen InSiGHT MSH6 v2.0 rules scope PP3, BP4, and BP7 to variant classes that do not include this coding frameshift.
NM_000179.3:c.3261dup produces NP_000170.1:p.(Phe1088LeufsTer5) / p.(F1088Lfs*5); therefore PP3, BP4, and BP7 are all not applicable in this group.
The exact variant notations were searched in the governing MSH6 full-text directory; no exact HCI-prior lookup row was found.
No criteria match.
Met · 2
PVS1Very strongVCEPMet, very strong: the frameshift creates a premature stop at approximately codon 1092, below the MSH6 VCEP cutoff of codon 1341.
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Reasoning
NM_000179.3:c.3261dup is a frameshift on the governing MSH6 transcript, producing NP_000170.1:p.(Phe1088LeufsTer5) / p.(F1088Lfs*5), with a premature termination codon at approximately codon 1092. The VCEP CSPEC rule assigns full PVS1 to a nonsense/frameshift variant introducing a PTC at or before codon 1341 in MSH6; the VCEP PVS1 decision-tree transcription likewise places MSH6 nonsense/frameshift variants at or before codon 1317 on the predicted-NMD path in the full PVS1 tier. Codon 1092 is below both governing cutoffs, the variant is in exon 5 rather than the last exon, and no named VCEP downgrade rule applies. The two named VCEP reference files were searched for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5; neither contains an exact variant row, so the pre-assigned answer is not being substituted from those tables.
VCEP rule
Nonsense/frameshift variant introducing Premature Termination Codon (PTC)<sup>a</sup> ≤ codon 1341 in _MSH6_. Refer to Appendix for details.
Evidence considered
Variant-level assessment: NM_000179.3:c.3261dup on the preferred transcript, exon 5, frameshift, NP_000170.1:p.(Phe1088LeufsTer5) / p.(F1088Lfs*5).
ClinGen InSiGHT MSH6 CSPEC v2.0 PVS1 entry: nonsense/frameshift PTC at or before codon 1341 in MSH6 receives the full PVS1 tier.
PVS1_DecisionTree_MMR.pdf, page 1: MSH6 nonsense/frameshift variants at or before codon 1317 on the predicted-NMD path receive PVS1.
PMID:18809606, Results, Table 1, Patients With Deleterious Mutations: patient 56838 is reported with MSH6 c.3261dupC, p.F1088LfsX5; this is variant-specific clinical occurrence, not the governing strength assignment.
Neither PVS1_DecisionTree_MMR.pdf nor VCEP-pilot-variants---MMR.xlsx contains an exact row for c.3261dup, p.Phe1088LeufsTer5, or p.F1088Lfs*5.
Still missing
PVS1_DecisionTree_MMR.pdf was searched for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5, but no exact variant entry was found.
VCEP-pilot-variants---MMR.xlsx was searched for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5, but no exact variant entry was found.
PP5SupportingVCEPNot applicable: the MSH6 VCEP explicitly prohibits PP5, regardless of pathogenic classifications reported by ClinVar or publications.
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Reasoning
Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
The VCEP CSPEC marks PP5 applicability as Not Applicable for this VCEP and states that this criterion is not for use.
PM2VCEPNot met: gnomAD v4.1 total AF is 0.0000565203, exceeding the PM2 threshold of <0.00002 (<1 in 50,000 alleles).
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Reasoning
PM2 is not met. The governing MSH6 VCEP requires an absent or extremely rare allele frequency below 0.00002 (<1 in 50,000 alleles) in gnomAD v4.1. This variant is present at total AF 0.0000565203 (91/1,610,042 alleles), and its gnomAD v4.1 Grpmax FAF is 0.00004271; both exceed 0.00002.
VCEP rule
Absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles ) in gnomAD v4 dataset
Evidence considered
gnomAD v4.1 variant 2-47803500-A-AC (NM_000179.3:c.3261dup): total AF 5.652026468874725e-05 from 91/1,610,042 alleles, 0 homozygotes, and Grpmax FAF 4.271e-05.
The VCEP pilot spreadsheet, which declares PM2 precedent, was searched under c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5; no matching row was present.
Still missing
VCEP-pilot-variants---MMR.xlsx was searched for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5; no matching variant row was found.
PP4VCEPNot met: the exact-variant CRC report showed instability in 2 of 5 markers, not the VCEP's MSI-H requirement, with no qualifying MSH6 protein-loss evidence.
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Reasoning
The governing PP4 supporting rule requires one CRC or endometrial MSI-H tumor using a standard 5-10-marker panel or tumor genome and/or MSH6-consistent protein loss. PMID:18809606 reports the exact variant in a sigmoid CRC with instability in only 2 of 5 markers, not MSI-H, and provides no qualifying MSH6 IHC loss. No patient-specific PP4 evidence meeting the moderate or strong thresholds was available. The CMMRD scoring table was searched and contains no entry for c.3261dup, p.Phe1088LeufsTer5, or p.F1088Lfs*5; the VCEP pilot table was also searched and contains no entry for this variant.
VCEP rule
1 CRC/Endometrial MSI-H tumor using a standard panel of 5-10 markers<sup>e</sup> or tumor genome **and/or** loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4.
Evidence considered
PMID:18809606, Results, Table 1, Patients With Deleterious Mutations: exact variant MSH6 c.3261dupC, p.F1088LfsX5 was reported in patient 56838, a 58-year-old woman with sigmoid colorectal cancer; the row records instability in 2 of 5 markers.
The study context was 500 unselected colorectal-cancer patients screened by MSI and IHC, followed by mismatch-repair-gene sequencing and MLPA; the extracted exact-variant row does not report MSI-H status or MSH6-consistent protein loss.
Table-for-CMMRD-diagnosis.pdf was searched across all three requested variant notations and has no variant-specific row; its scoring system concerns CMMRD clinical features rather than supplying a qualifying PP4 tumor result for this case.
VCEP-pilot-variants---MMR.xlsx was searched across all three requested variant notations and has no variant-specific row.
Still missing
Table-for-CMMRD-diagnosis.pdf searched for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5; no variant entry found.
VCEP-pilot-variants---MMR.xlsx searched for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5; no variant entry found.
No patient-specific MSH6-consistent IHC result or tumor-genome result meeting the PP4 rule was available.
BA1VCEPNot met: gnomAD v4.1 Grpmax FAF is 0.00004271 (0.004271%), below the BA1 threshold of ≥0.0022 (0.22%).
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Reasoning
BA1 is not met. The governing MSH6 VCEP threshold requires a gnomAD v4 Grpmax filtering allele frequency of at least 0.0022 (0.22%) and exclusion as a founder pathogenic variant. gnomAD v4.1 reports a Grpmax FAF of 0.00004271 (0.004271%), with total AF 0.0000565203 and 0 homozygotes; the observed Grpmax FAF is below the threshold, so the criterion is not satisfied.
VCEP rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%) and variant is excluded as founder pathogenic variant.
Evidence considered
gnomAD v4.1 variant 2-47803500-A-AC (NM_000179.3:c.3261dup): total AF 5.65203e-05 (91/1,610,042 alleles), 0 homozygotes, and Grpmax FAF 4.271e-05.
The VCEP pilot spreadsheet was searched under c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5; no matching row was present.
Still missing
VCEP-pilot-variants---MMR.xlsx was searched for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5; no matching variant row was found.
BS1VCEPNot met: gnomAD v4.1 Grpmax FAF is 0.00004271, below the BS1 interval beginning at ≥0.00022 (0.022%).
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Reasoning
BS1 is not met. The governing MSH6 VCEP threshold requires a gnomAD v4 Grpmax filtering allele frequency of at least 0.00022 and less than 0.0022 (0.022–0.22%), with exclusion as a founder pathogenic variant. gnomAD v4.1 reports a Grpmax FAF of 0.00004271 (0.004271%), which is below the lower bound of the BS1 interval.
VCEP 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
gnomAD v4.1 variant 2-47803500-A-AC (NM_000179.3:c.3261dup): Grpmax FAF 4.271e-05 (0.004271%), below 0.00022; total AF 5.65203e-05 and 0 homozygotes.
The VCEP pilot spreadsheet was searched under c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5; no matching row was present.
Still missing
VCEP-pilot-variants---MMR.xlsx was searched for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5; no matching variant row was found.
PS2VCEPNot assessed: one affected proband is reported, but parental testing and the de novo points required by the VCEP are not documented.
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Reasoning
The exact-variant report documents one affected proband with MSH6 c.3261dupC, but it does not document absence of the variant in both parents, parental testing, confirmed maternity and paternity, or a de novo point assignment. Therefore the VCEP's PS2 de novo-point thresholds cannot be evaluated.
Evidence considered
PMID:18809606, Results, Table 1, Patients With Deleterious Mutations: patient 56838 is listed with MSH6 c.3261dupC, p.F1088LfsX5 and sigmoid colorectal cancer; the report identifies an affected proband but does not provide parental testing or de novo status.
The VCEP PS2 framework assigns strength from a documented de novo point total; no such total is available for this case.
Still missing
Parental genotypes and confirmation of biological parentage are unavailable.
PS3VCEPNot assessed: no variant-specific calibrated functional-assay result or qualifying functional odds were found; the exact variant report only documents MSI in 2 of 5 markers.
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Reasoning
The VCEP makes PS3 applicable through calibrated functional assays or the MMR functional-assay flowchart. The Functional-assay-SVI-documentation-MMR.xlsx table was searched for c.3261dup, c.3261dupC, p.Phe1088LeufsTer5, p.F1088Lfs*5, and p.F1088LfsX5, with no variant-specific entry. The Functional-assay-flowchart.pdf text was also searched for the same notations, with no entry. The exact-variant literature record in PMID:18809606 reports MSH6 c.3261dupC/p.F1088LfsX5 in a colorectal-cancer cohort and microsatellite instability in 2 of 5 markers, but it does not report a calibrated functional assay, functional odds, or a qualifying MMR functional-assay-flowchart result. Therefore PS3 cannot be assigned from the available VCEP-governed evidence.
VCEP rule
Calibrated functional assays with functional odds forpathogenicity > 18.7...Calibrated functional assays with functional odds for pathogenicity >4.3 and <= 18.7
OR
MMR function defect following functional assay flowchart*
OR
Variants with monoallelic expression: complete loss of expression (<10% of wild-type in cDNA without puromycin) of the variant allele. Full-length transcript should be analysed with and without NMD block....Calibrated functional odds for pathogenicity >2.08 and <= 4.3
Evidence considered
Functional-assay-SVI-documentation-MMR.xlsx, sheet MMR assays: approved calibrated assay classes and validation-control rows were reviewed; the table contains no row keyed to this variant.
Functional-assay-flowchart.pdf, page 1: the flowchart describes calibrated assays and selected in-frame/missense or splice/silent/intronic pathways, but provides no variant-specific result for this frameshift.
PMID:18809606, Results, Table 1, Patients With Deleterious Mutations: exact variant reported as MSH6 c.3261dupC p.F1088LfsX5 in patient 56838, with instability in 2 of 5 markers; no calibrated functional assay or functional odds reported.
The exact notations c.3261dup, c.3261dupC, p.Phe1088LeufsTer5, p.F1088Lfs*5, and p.F1088LfsX5 were searched in both governing VCEP functional-assay files with no matching entry.
Still missing
Functional-assay-SVI-documentation-MMR.xlsx: no entry found for c.3261dup, c.3261dupC, p.Phe1088LeufsTer5, p.F1088Lfs*5, or p.F1088LfsX5.
Functional-assay-flowchart.pdf: no entry found for c.3261dup, c.3261dupC, p.Phe1088LeufsTer5, p.F1088Lfs*5, or p.F1088LfsX5.
No variant-specific calibrated functional odds or qualifying functional assay readout is available in the reviewed case evidence.
PM3VCEPNot assessed: the reported proband has c.3261dup, but no second MSH6 pathogenic variant, phase, or CMMRD features are documented for PM3 point assignment.
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Reasoning
The MSH6 VCEP PM3 rule requires co-occurrence of this variant with a known pathogenic or likely pathogenic variant in the same gene in a patient with clinical features consistent with CMMRD. A single affected proband report documents NM_000179.3:c.3261dup (c.3261dupC; p.F1088LfsX5) in a 58-year-old woman with colorectal cancer, but it does not report a second MSH6 pathogenic/likely pathogenic variant, phase, or CMMRD features. Therefore no PM3 points can be assigned from the available evidence, and PM3 cannot be assessed.
VCEP rule
Co-occurrence with a known pathogenic/likely pathogenic sequence variant in the same gene in a patient with clinical features consistent with CMMRD as per Aronson et al 2022 - Refer to “Table for CMMRD diagnosis.pdf”. For MLH1 variants - the variant has to meet PM2\_Supporting criteria. Classification/zygosity of other variant: Pathogenic/Likely Pathogenic in trans: 1.0 point; Pathogenic/Likely Pathogenic - phase unknown: 0.5 points Sum all cases with the above evidence to determine the PM3 strength.
Evidence considered
ClinGen InSiGHT MSH6 specification v2.0 PM3 instructions: 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 and phase unknown = 0.5 points.
PMID:18809606, Results, Table 1, Patients With Deleterious Mutations: patient 56838, a 58-year-old woman with sigmoid colorectal cancer, carried MSH6 c.3261dupC, p.F1088LfsX5; the extracted report contains no second MSH6 variant or phase information.
The available observation is one affected proband report and does not establish biallelic MSH6 disease or CMMRD features.
Still missing
A known pathogenic or likely pathogenic second MSH6 variant in the same patient
Confirmed trans phase or explicitly documented phase uncertainty
Clinical features demonstrating CMMRD according to the VCEP-referenced CMMRD table
PP1VCEPNot assessed: no pedigree-level segregation dataset or combined Bayes Likelihood Ratio is available to compare with the VCEP thresholds.
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Reasoning
The exact-variant report documents an affected proband, not a pedigree-level segregation analysis. No combined Bayes Likelihood Ratio, informative meioses, tested relatives, carrier or non-carrier disease statuses, or validated family-level segregation dataset is available, so the VCEP PP1 thresholds cannot be applied.
Evidence considered
PMID:18809606, Results, Table 1, Patients With Deleterious Mutations: the exact variant is reported in one patient with sigmoid colorectal cancer; the extracted report provides no family pedigree, tested relatives, or segregation result.
No combined Bayes Likelihood Ratio or qualifying family count is reported in the available case evidence.
Still missing
A pedigree with tested affected and unaffected relatives is unavailable.
Informative meioses and a combined Bayes Likelihood Ratio are unavailable.
The available proband report does not establish co-segregation.
BS2VCEPNot assessed: no qualifying in-trans co-occurrence, phase confirmation, cancer-age condition, or CMMRD-status documentation is available.
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Reasoning
BS2 cannot be assessed from the available evidence. The VCEP requires documented co-occurrence in trans with a known pathogenic sequence variant in MSH6 in a patient meeting the specified cancer-age condition, absence of CMMRD manifestations, and phase confirmation through parental or offspring testing. The case evidence contains no qualifying co-occurrence, phase, or CMMRD-status documentation.
VCEP 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 other LS cancer above the median age of onset for that cancer in LS<sup>d</sup>), and who has no previous or current evidence of clinical manifestations of CMMRD as per Aronson et al 2022 (Refer to 'Table for CMMRD diagnosis.pdf'). Confirmation of phase requires testing of parents or offspring.
Evidence considered
The case evidence documents population observations for the variant but does not document a patient with this variant in trans with a known pathogenic MSH6 sequence variant, confirmed phase, the required cancer-age condition, and absence of CMMRD manifestations.
The VCEP pilot spreadsheet was searched under c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5; no matching row was present.
Still missing
No qualifying in-trans co-occurrence record, phase testing, or CMMRD-status evidence was identified in the case evidence.
VCEP-pilot-variants---MMR.xlsx was searched for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5; no matching variant row was found.
BS3VCEPNot assessed: no variant-specific proficient-function result or benign functional odds were found, while the exact report showed MSI in 2 of 5 tumor markers.
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Reasoning
The VCEP makes BS3 applicable through calibrated functional assays with benign functional odds or variant-specific proficient function under the MMR functional-assay flowchart. The Functional-assay-SVI-documentation-MMR.xlsx table was searched for c.3261dup, c.3261dupC, p.Phe1088LeufsTer5, p.F1088Lfs*5, and p.F1088LfsX5, with no variant-specific entry. The Functional-assay-flowchart.pdf text was likewise searched with no entry. PMID:18809606 reports the exact variant and tumor microsatellite instability in 2 of 5 markers, not proficient protein or mRNA function and not a calibrated benign functional result. Consequently BS3 cannot be assigned.
VCEP rule
Calibrated functional assays with functional odds for Pathogenicity <= 0.05
OR
Synonymous substitutions and intronic variants with no associated mRNA aberration (either splicing or allelic imbalance) as determined by laboratory assays conducted with nonsense-mediated decay inhibition. Whenever abnormal transcripts are identified at similar levels in controls they will be considered naturally occurring isoforms and not mRNA aberrations....Calibrated functional assays with functional odds for Pathogenicity >0.05 & <=0.48
OR
Variant-specific proficient function in protein and mRNA-based lab assays as per MMR functional assay flowchart.
Evidence considered
Functional-assay-SVI-documentation-MMR.xlsx, sheet MMR assays: approved calibrated assay classes and benign thresholds were reviewed; the table contains no row keyed to this variant.
Functional-assay-flowchart.pdf, page 1: proficient-function pathways require specific assay findings, none of which are reported for this variant.
PMID:18809606, Results, Table 1, Patients With Deleterious Mutations: exact variant reported as MSH6 c.3261dupC p.F1088LfsX5, with instability in 2 of 5 markers; no proficient-function assay or benign functional odds reported.
The exact notations c.3261dup, c.3261dupC, p.Phe1088LeufsTer5, p.F1088Lfs*5, and p.F1088LfsX5 were searched in both governing VCEP functional-assay files with no matching entry.
Still missing
Functional-assay-SVI-documentation-MMR.xlsx: no entry found for c.3261dup, c.3261dupC, p.Phe1088LeufsTer5, p.F1088Lfs*5, or p.F1088LfsX5.
Functional-assay-flowchart.pdf: no entry found for c.3261dup, c.3261dupC, p.Phe1088LeufsTer5, p.F1088Lfs*5, or p.F1088LfsX5.
No variant-specific proficient protein/mRNA assay result or calibrated benign functional odds is available in the reviewed case evidence.
BS4VCEPNot assessed: no non-segregation observations or combined Bayes Likelihood Ratio is documented for comparison with the VCEP thresholds.
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Reasoning
No non-segregation pedigree, unaffected carrier, affected non-carrier, or combined Bayes Likelihood Ratio for lack of co-segregation is documented. The VCEP BS4 thresholds cannot be evaluated.
Evidence considered
The available case evidence contains no tested relatives with documented discordant genotype-phenotype findings and no combined Bayes Likelihood Ratio for lack of co-segregation.
Still missing
No pedigree-level non-segregation data are available.
No combined Bayes Likelihood Ratio for lack of co-segregation is available.
BP5VCEPNot assessed: the only exact-variant tumor report showed instability in 2 of 5 markers, not MSS, and lacked the VCEP-required alternate molecular-basis result.
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Reasoning
The VCEP BP5 rule requires either 2 or 3 qualifying tumors with MSS, no MMR-protein loss, or inconsistent MMR loss, or one BRAF V600E/MLH1-methylation result. The available exact-variant report describes a CRC with instability in 2 of 5 markers, not MSS, and does not provide the required alternate-molecular-basis findings. No qualifying BRAF V600E or MLH1-methylation result was available, so BP5 cannot be assessed.
VCEP rule
2 or 3 tumors: CRC/Endometrial tumors with MSS and/or no loss of MMR protein expression and/or LS spectrum tumors<sup>d</sup> with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation.
OR
1 BRAF V600E (Colon only)/_MLH1_ methylation (in LS spectrum tumor only) with MSI-H/_MLH1_ loss.
Evidence considered
The VCEP rule requires 2 or 3 tumors with MSS and/or no loss of MMR protein expression and/or inconsistent protein loss, or one BRAF V600E/MLH1-methylation result.
PMID:18809606, Results, Table 1, Patients With Deleterious Mutations: exact variant in one sigmoid CRC with instability in 2 of 5 markers; this is not documented as MSS and does not establish an alternate molecular basis.
Still missing
No qualifying MSS or MMR-protein-expression results for 2 or 3 tumors were available.
No qualifying BRAF V600E or MLH1-methylation result was available.
Not applicable · 14· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: c.3261dup is a frameshift, whereas the VCEP PS1 rule requires a same-amino-acid missense substitution or non-canonical splice-nucleotide variant.
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Reasoning
PS1 is not applicable because the case variant is a frameshift, NP_000170.1:p.(Phe1088LeufsTer5), not a predicted missense substitution and not a variant affecting a non-canonical splice nucleotide. The VCEP PS1 rule is restricted to those two routes; the exact-variant literature finding in PMID:18809606 does not create a same-amino-acid-change PS1 route.
VCEP rule
A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic (not a predicted or confirmed splice defect). ... Variants affecting the same non-canonical splice nucleotide as a confirmed Pathogenic splice variant with similar or worse splicing in silico prediction using SpliceAI.
Evidence considered
The case consequence is frameshift with protein consequence NP_000170.1:p.(Phe1088LeufsTer5), so it does not meet either VCEP PS1 route.
PMID:18809606 reports the exact frameshift as MSH6 c.3261dupC, p.F1088LfsX5 in Table 1, but this is not a different nucleotide change encoding the same amino-acid substitution.
PS4VCEPNot applicable: the MSH6 VCEP explicitly excludes PS4 from MMR classification because tumor IHC evidence is evaluated through PP4 instead.
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Reasoning
The MSH6 VCEP explicitly marks PS4 as not applicable because tumor IHC data are available for MMR classification and PP4 is used instead; therefore no case-control OR, confidence interval, or proband-counting PS4 assessment is permitted. Literature was checked, including the literature_pass.json PS4 index and the exact-variant report in PMID:18809606, but those findings cannot override the VCEP applicability rule.
VCEP rule
Due to the availability of tumor IHC data for variant classification (see PP4), PS4 has not been utilized for MMR variant classification using proband counting.
Evidence considered
The VCEP CSPEC marks PS4 applicability as Not applicable and states: Due to the availability of tumor IHC data for variant classification (see PP4), PS4 has not been utilized for MMR variant classification using proband counting.
The literature_pass.json PS4 index was reviewed; PMID:18809606 reports the exact variant in one colorectal-cancer patient, but PS4 remains unavailable under the governing VCEP rule.
PM1VCEPNot applicable: the VCEP excludes PM1 because no recognized hotspots are used and pathogenic variants are generalized across MMR functional domains.
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Reasoning
PM1 is not applicable under the MSH6 VCEP specification. The VCEP states that no recognized mutational hotspots are used and that the distribution of pathogenic variants is generalized across MMR functional domains. The governing vcep_materials.json domain_tables key is empty. The separately searched MMR-Functional-domains.pdf.txt places residue 1088 within the MSH6 lever domain (981-1132), but that domain location cannot override the VCEP's explicit PM1 non-applicability.
VCEP rule
There are no recognized mutational hot spots that could be used for classification purposes. While there are functional domains in the MMR genes, the distribution of pathogenic variants is generalized over all the domains (unpublished data).
Evidence considered
The VCEP PM1 instructions state: no recognized mutational hotspots can be used, and pathogenic variants are generalized over all MMR functional domains.
MMR-Functional-domains.pdf.txt lists MSH6 lever residues 981-1132, which includes residue 1088; vcep_materials.json has no domain_tables entry, and the VCEP PM1 applicability remains Not applicable.
Still missing
No entry for c.3261dup, p.Phe1088LeufsTer5, or p.F1088Lfs*5 was found in MMR-Functional-domains.pdf.txt.
PM4VCEPNot applicable: the MSH6 VCEP excludes PM4, which concerns in-frame protein-length changes, while this variant is a frameshift.
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Reasoning
The MSH6 VCEP explicitly marks PM4 as not applicable. Its instruction limits protein-length-change use to in-frame variants, whereas this variant is a frameshift with a premature termination codon rather than an in-frame deletion, insertion, or stop-loss change.
VCEP rule
Protein length change from an in-frame variant is not used due to lack of evidence.
Evidence considered
ClinGen InSiGHT MSH6 CSPEC v2.0 marks PM4 as Not Applicable and states: Protein length change from an in-frame variant is not used due to lack of evidence.
Variant-level assessment classifies NM_000179.3:c.3261dup as a frameshift producing p.(Phe1088LeufsTer5), not an in-frame variant.
PM5N/ANot applicable: c.3261dup produces a frameshift, while the VCEP PM5 rule requires a missense change and a different classified missense change at the same residue.
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Reasoning
PM5 is not applicable because the case variant is a frameshift, not a missense change at an amino-acid residue. The VCEP PM5 rules require a missense change and a different VCEP-classified missense change at the same residue; no such PM5 route applies to NP_000170.1:p.(Phe1088LeufsTer5).
VCEP rule
Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level and not due to aberrant splicing. Only use PM5 if PP3 is supporting for the missense change. Use PM5_Supporting if other variant is Likely Pathogenic due to a missense alteration. ... Missense change at an amino acid residue where a different missense change was classified as Likely Pathogenic on the protein level and not due to aberrant splicing. Only use PM5_Supporting if PP3 is supporting for the missense change. Use PM5 if other variant is Pathogenic due to a missense alteration.
Evidence considered
The case variant is a frameshift, so the VCEP PM5 missense-only rule cannot apply.
The case PM5 candidate collection found no applicable same-residue missense comparator, consistent with the variant being outside the criterion's named variant type.
PP2VCEPNot applicable: the MSH6 VCEP marks PP2 Not applicable, and its stated rule concerns missense variation while this variant is a frameshift.
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Reasoning
PP2 is explicitly marked Not applicable by the MSH6 VCEP. Its instruction limits PP2 to the missense-variation mechanism, and this case variant is a frameshift.
VCEP rule
Missense variant in a gene with low rate of benign missense changes does not apply.
Evidence considered
The VCEP PP2 entry is marked Not applicable and states that missense variation does not apply; the case variant is a frameshift.
PP3N/ANot applicable: c.3261dup is a frameshift, while PP3 covers missense HCI-prior evidence or non-canonical splice defects with SpliceAI delta score >= 0.2.
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Reasoning
The VCEP PP3 rule is limited to either missense variants evaluated with the HCI prior or predicted splice defects at non-canonical splicing nucleotides using SpliceAI. NM_000179.3:c.3261dup is a frameshift producing NP_000170.1:p.(Phe1088LeufsTer5), not a missense variant or a non-canonical splice-site variant, so PP3 is not applicable before any predictor score is considered. The exact variant was searched in HCI-PRIORS-MSH6.txt.txt and no entry was found; that table is declared for missense substitutions and cannot extend PP3 to this frameshift.
VCEP rule
Missense variant with HCI prior probability for pathogenicity >0.81 as per [https://hci-priors.hci.utah.edu/PRIORS](https://hci-priors.hci.utah.edu/PRIORS) ... Missense variant with HCI prior probability for pathogenicity >0.68 & <=0.81 as per [https://hci-priors.hci.utah.edu/PRIORS](https://hci-priors.hci.utah.edu/PRIORS) ... Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.
Evidence considered
ClinGen InSiGHT MSH6 v2.0 PP3 rule scope: the HCI-prior path is for missense variants, and the alternative SpliceAI path is for predicted splice defects at non-canonical splicing nucleotides.
Variant normalization: NM_000179.3:c.3261dup produces NP_000170.1:p.(Phe1088LeufsTer5) / p.(F1088Lfs*5), establishing a frameshift consequence rather than a missense or non-canonical splice-site variant.
Exact-variant search of HCI-PRIORS-MSH6.txt.txt for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5 found no matching row.
Still missing
No exact entry for c.3261dup, p.Phe1088LeufsTer5, or p.F1088Lfs*5 was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MSH6/fulltext/HCI-PRIORS-MSH6.txt.txt; the file is a missense lookup table.
BP1VCEPNot applicable: the MSH6 VCEP marks BP1 Not applicable, and its stated rule concerns missense variants while this variant is a frameshift.
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Reasoning
BP1 is explicitly marked Not applicable by the MSH6 VCEP. Its instruction concerns missense variants in a loss-of-function disease mechanism, whereas this case variant is itself a frameshift.
VCEP rule
Missense variant in a gene where only loss of function causes disease is not applicable.
Evidence considered
The VCEP BP1 entry is marked Not applicable and states that missense variants in a gene where only loss of function causes disease are not applicable; the case variant is a frameshift.
BP3VCEPNot applicable: the MSH6 VCEP marks BP3 as not applicable, and this variant is a truncating frameshift rather than an in-frame repeat-region indel.
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Reasoning
The MSH6 VCEP CSPEC entry explicitly marks BP3 as not applicable. This is a coding frameshift with a premature termination codon, not an in-frame deletion or insertion in a repetitive region.
VCEP rule
Not Applicable
Evidence considered
ClinGen InSiGHT MSH6 CSPEC v2.0 explicitly lists BP3 applicability as Not Applicable.
Variant-level assessment classifies NM_000179.3:c.3261dup as a frameshift producing p.(Phe1088LeufsTer5), so the in-frame repeat-region BP3 concept does not apply.
BP4N/ANot applicable: c.3261dup is a frameshift, whereas BP4 covers missense HCI-prior probability <0.11 or intronic/synonymous SpliceAI delta score <= 0.1.
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Reasoning
The VCEP BP4 rule applies either to missense variants with an HCI-prior probability below 0.11 or to intronic and synonymous variants for which SpliceAI predicts no splicing impact with delta score <= 0.1. NM_000179.3:c.3261dup is a frameshift producing NP_000170.1:p.(Phe1088LeufsTer5), so neither BP4 path applies; a low splice-impact prediction cannot negate its truncating protein consequence. The exact variant was searched in HCI-PRIORS-MSH6.txt.txt and no entry was found; that table is declared for missense substitutions.
VCEP rule
Missense variant with HCI-prior probability of pathogenicity <0.11 as per https://hci-priors.hci.utah.edu/PRIORS ... OR ... For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.
Evidence considered
ClinGen InSiGHT MSH6 v2.0 BP4 rule scope: the HCI-prior path is for missense variants, while the SpliceAI no-impact path is for intronic and synonymous variants.
Variant normalization: NM_000179.3:c.3261dup produces NP_000170.1:p.(Phe1088LeufsTer5) / p.(F1088Lfs*5), establishing a frameshift consequence outside both BP4 paths.
Exact-variant search of HCI-PRIORS-MSH6.txt.txt for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5 found no matching row.
Still missing
No exact entry for c.3261dup, p.Phe1088LeufsTer5, or p.F1088Lfs*5 was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MSH6/fulltext/HCI-PRIORS-MSH6.txt.txt; the file is a missense lookup table.
BP6VCEPNot applicable: the MSH6 VCEP explicitly prohibits BP6, so no benign source assertion can activate this criterion.
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Reasoning
The MSH6 VCEP explicitly marks BP6 as not applicable for this VCEP and states that the criterion is not for use. A reputable-source benign assertion cannot be converted into BP6 under this governing specification.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
The VCEP CSPEC marks BP6 applicability as Not Applicable for this VCEP and states that this criterion is not for use.
BP7N/ANot applicable: c.3261dup is a coding frameshift, while BP7 is restricted to synonymous or intronic variants at or beyond -21/+7.
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Reasoning
The VCEP BP7 rule is restricted to synonymous (silent) or intronic variants at or beyond -21/+7 (5'/3' exonic). NM_000179.3:c.3261dup is a coding frameshift producing NP_000170.1:p.(Phe1088LeufsTer5), not a synonymous or intronic variant, so BP7 is not applicable.
VCEP rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.
Evidence considered
ClinGen InSiGHT MSH6 v2.0 BP7 rule: synonymous or intronic variant scope at or beyond -21/+7.
Variant normalization identifies NM_000179.3:c.3261dup as a coding frameshift producing NP_000170.1:p.(Phe1088LeufsTer5) / p.(F1088Lfs*5), not a synonymous or intronic variant.
AF 5.7e-05 · 91 / 1,610,042 alleles · 0 hom · FAF 4.3e-05
European (Finnish)17 / 63,170
0.00027
European (non-Finnish)63 / 1,178,232
5.3e-05
African/African American3 / 74,254
4e-05
Ashkenazi Jewish1 / 29,570
3.4e-05
South Asian3 / 90,962
3.3e-05
Remaining individuals2 / 62,372
3.2e-05
East Asian1 / 44,814
2.2e-05
Admixed American1 / 59,686
1.7e-05
0 alternate alleles recorded in 2 other groups: Amish, Middle Eastern.
gnomAD v2.1
AF 6.1e-05 · 17 / 280,876 alleles · 0 hom · FAF 3.4e-05
Remaining individuals2 / 7,178
0.00028
African/African American3 / 24,758
0.00012
European (Finnish)2 / 25,028
8e-05
European (non-Finnish)8 / 127,934
6.3e-05
South Asian1 / 30,512
3.3e-05
Admixed American1 / 35,296
2.8e-05
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, East Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.65203e-05; MAF= 0.00565%, 91/1610042 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000269115; MAF= 0.02691%, 17/63170 alleles, homozygotes = 0); grpmax FAF= 4.271e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.05249e-05; MAF= 0.00605%, 17/280876 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000278629; MAF= 0.02786%, 2/7178 alleles, homozygotes = 0); grpmax FAF= 3.449e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -80 bp
0.010
SpliceAI acceptor gainat +94 bp
0.070
SpliceAI donor lossat +185 bp
0.001
SpliceAI donor gainat -229 bp
0.029
Pangolin splice lossmagnitude shown
-0.069
Pangolin splice gain
0.056
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: c.3261dup is a frameshift, while PP3 covers missense HCI-prior evidence or non-canonical splice defects with SpliceAI delta score >= 0.2.
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Reasoning
The VCEP PP3 rule is limited to either missense variants evaluated with the HCI prior or predicted splice defects at non-canonical splicing nucleotides using SpliceAI. NM_000179.3:c.3261dup is a frameshift producing NP_000170.1:p.(Phe1088LeufsTer5), not a missense variant or a non-canonical splice-site variant, so PP3 is not applicable before any predictor score is considered. The exact variant was searched in HCI-PRIORS-MSH6.txt.txt and no entry was found; that table is declared for missense substitutions and cannot extend PP3 to this frameshift.
VCEP rule
Missense variant with HCI prior probability for pathogenicity >0.81 as per [https://hci-priors.hci.utah.edu/PRIORS](https://hci-priors.hci.utah.edu/PRIORS) ... Missense variant with HCI prior probability for pathogenicity >0.68 & <=0.81 as per [https://hci-priors.hci.utah.edu/PRIORS](https://hci-priors.hci.utah.edu/PRIORS) ... Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.
Evidence considered
ClinGen InSiGHT MSH6 v2.0 PP3 rule scope: the HCI-prior path is for missense variants, and the alternative SpliceAI path is for predicted splice defects at non-canonical splicing nucleotides.
Variant normalization: NM_000179.3:c.3261dup produces NP_000170.1:p.(Phe1088LeufsTer5) / p.(F1088Lfs*5), establishing a frameshift consequence rather than a missense or non-canonical splice-site variant.
Exact-variant search of HCI-PRIORS-MSH6.txt.txt for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5 found no matching row.
Still missing
No exact entry for c.3261dup, p.Phe1088LeufsTer5, or p.F1088Lfs*5 was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MSH6/fulltext/HCI-PRIORS-MSH6.txt.txt; the file is a missense lookup table.
BP4N/ANot applicable: c.3261dup is a frameshift, whereas BP4 covers missense HCI-prior probability <0.11 or intronic/synonymous SpliceAI delta score <= 0.1.
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Reasoning
The VCEP BP4 rule applies either to missense variants with an HCI-prior probability below 0.11 or to intronic and synonymous variants for which SpliceAI predicts no splicing impact with delta score <= 0.1. NM_000179.3:c.3261dup is a frameshift producing NP_000170.1:p.(Phe1088LeufsTer5), so neither BP4 path applies; a low splice-impact prediction cannot negate its truncating protein consequence. The exact variant was searched in HCI-PRIORS-MSH6.txt.txt and no entry was found; that table is declared for missense substitutions.
VCEP rule
Missense variant with HCI-prior probability of pathogenicity <0.11 as per https://hci-priors.hci.utah.edu/PRIORS ... OR ... For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.
Evidence considered
ClinGen InSiGHT MSH6 v2.0 BP4 rule scope: the HCI-prior path is for missense variants, while the SpliceAI no-impact path is for intronic and synonymous variants.
Variant normalization: NM_000179.3:c.3261dup produces NP_000170.1:p.(Phe1088LeufsTer5) / p.(F1088Lfs*5), establishing a frameshift consequence outside both BP4 paths.
Exact-variant search of HCI-PRIORS-MSH6.txt.txt for c.3261dup, p.Phe1088LeufsTer5, and p.F1088Lfs*5 found no matching row.
Still missing
No exact entry for c.3261dup, p.Phe1088LeufsTer5, or p.F1088Lfs*5 was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MSH6/fulltext/HCI-PRIORS-MSH6.txt.txt; the file is a missense lookup table.
BP7N/ANot applicable: c.3261dup is a coding frameshift, while BP7 is restricted to synonymous or intronic variants at or beyond -21/+7.
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Reasoning
The VCEP BP7 rule is restricted to synonymous (silent) or intronic variants at or beyond -21/+7 (5'/3' exonic). NM_000179.3:c.3261dup is a coding frameshift producing NP_000170.1:p.(Phe1088LeufsTer5), not a synonymous or intronic variant, so BP7 is not applicable.
VCEP rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.
Evidence considered
ClinGen InSiGHT MSH6 v2.0 BP7 rule: synonymous or intronic variant scope at or beyond -21/+7.
Variant normalization identifies NM_000179.3:c.3261dup as a coding frameshift producing NP_000170.1:p.(Phe1088LeufsTer5) / p.(F1088Lfs*5), not a synonymous or intronic variant.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
7 paper records listed. 1 cited in the classification.
Cited in the classification
Feasibility of screening for Lynch syndrome among patients with colorectal cancer.
The paper explicitly reports this MSH6 germline frameshift variant as MSH6 c.3261dupC, p.F1088LfsX5 in patient 56838, a 58-year-old woman with sigmoid colorectal cancer. The variant was identified among 18 probands with deleterious mismatch-repair-gene mutations in a cohort of 500 unselected patients with colorectal cancer.
56838 F 58 Sigmoid N N 2 5 MSH6 c.3261dupC p.F1088LfsX5
Location Results, Table 1, Patients With Deleterious Mutations
Context Cohort of 500 unselected patients with colorectal cancer screened by microsatellite instability testing and immunohistochemistry; patients with MSI-positive tumors or abnormal immunohistochemistry underwent full mismatch-repair-gene analysis by sequencing and multiplex ligation-dependent probe amplification.
Other recorded publications
Molecular analysis of familial endometrial carcinoma: a manifestation of hereditary nonpolyposis colorectal cancer or a separate syndrome?
Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium.
Very low prevalence of germline MSH6 mutations in hereditary non-polyposis colorectal cancer suspected patients with colorectal cancer without microsatellite instability.
The extracted paper does not explicitly mention MSH6 c.3261dup or p.(F1088Lfs*5); it reports gene-level MSH6 mutation findings in MSI-high and non-MSI-high tumors.
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= 5.65203e-05; MAF= 0.00565%, 91/1610042 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000269115; MAF= 0.02691%, 17/63170 alleles, homozygotes = 0); grpmax FAF= 4.271e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.05249e-05; MAF= 0.00605%, 17/280876 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000278629; MAF= 0.02786%, 2/7178 alleles, homozygotes = 0); grpmax FAF= 3.449e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (50 clinical laboratories) and as pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 89364)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52273592, n = 125 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.