About RET
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RET c.2434del, p.Leu812CysfsTer57
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_020975.5:c.2434del is a frameshift variant in exon 14 of 20, predicted to produce a premature termination codon at position 868 (p.Leu812CysfsTer57) and trigger nonsense-mediated decay. RET loss-of-function is an established mechanism for Hirschsprung disease. Under ClinGen PVS1 recommendations (PMC6185798), this null variant qualifies for PVS1 at very strong strength.
PM2Moderate
PM2 · moderate
NM_020975.5:c.2434del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under generic ACMG rules, PM2 applies at moderate strength for variants with allele frequency below 0.1% in all population databases.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 17 not met · 1 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_020975.5:c.2434del is a frameshift variant in exon 14 of 20, predicted to cause a premature termination codon (p.Leu812CysfsTer57) and trigger nonsense-mediated decay.
RET loss-of-function is an established disease mechanism for Hirschsprung disease, meeting PVS1 at very strong strength under ClinGen SVI PVS1 recommendations (PMC6185798).
The variant truncates the RET tyrosine kinase domain (aa 724-1016) at codon 868, removing the activation loop and C-terminal tail. This domain is a critical functional domain characterized in the literature, meeting PM1 at moderate strength.
The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting PM2 at moderate strength under generic ACMG allele frequency thresholds.
No pathogenic benign criteria are met. The variant is absent from ClinVar, has no functional studies, and lacks segregation or case-control data.
Under generic ACMG/AMP 2015 combination rules (Richards et al. 2015), 1 very strong criterion (PVS1) plus 2 moderate criteria (PM1, PM2) meets the threshold for Pathogenic classification.
No criteria match.
Met · 2
PVS1 Very strongNM_020975.5:c.2434del is a frameshift variant in exon 14 of 20, predicted to produce a premature termination codon at position 868 (p.Leu812CysfsTer57) and trigger nonsense-mediated decay. RET loss-of-function is an established mechanism for Hirschsprung disease. Under ClinGen PVS1 recommendations (PMC6185798), this null variant qualifies for PVS1 at very strong strength. Details ▾Hide ▴
Evidence considered
- Frameshift at c.2434 in exon 14 of 20 exons
- predicted to trigger NMD
- RET loss-of-function is an established disease mechanism for Hirschsprung disease
- Absent from all population databases
Still missing
- Transcript NM_020975.5 is RefSeq select but not MANE
- confirm transcript relevance for the clinical indication
Sources
PM2 ModerateNM_020975.5:c.2434del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under generic ACMG rules, PM2 applies at moderate strength for variants with allele frequency below 0.1% in all population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0
Sources
Not met · 17 · evaluated, threshold not reached
PS2 No de novo observation has been reported for NM_020975.5:c.2434del. No literature or clinical data document a confirmed de novo occurrence. Details ▾Hide ▴
Still missing
- No parental or proband data available
PS3 No functional studies have been performed on NM_020975.5:c.2434del or on a systematically characterized range that includes codon 812. REVEL and BayesDel are not available for non-SNV variants. No variant-specific experimental data exist in the curated literature. Details ▾Hide ▴
Still missing
- No functional data for this variant or a systematically characterized range encompassing codon 812
PS4 No case-control or prevalence data are available for this variant. The variant is absent from ClinVar and has not been observed in affected individuals in the curated literature. Details ▾Hide ▴
Still missing
- No affected individual counts available
PM6 No de novo observation has been reported for NM_020975.5:c.2434del. PM6 requires a de novo observation without confirmed parentage, which is not available. Details ▾Hide ▴
Still missing
- No de novo reports in literature or clinical databases
PP1 No segregation data are available for NM_020975.5:c.2434del. PP1 requires evidence of cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Still missing
- No family or segregation studies available
PP3 SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not available for this non-SNV variant. No in silico evidence supports pathogenicity. PP3 cannot be applied in the absence of multiple lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00 (no splice impact)
- REVEL and BayesDel not applicable for non-SNV variants
Sources
PP4 No patient phenotype or clinical data are available for this case. PP4 requires the patient's phenotype or family history to be highly specific for a disease associated with the gene. Details ▾Hide ▴
Still missing
- No proband phenotype data provided
PP5 NM_020975.5:c.2434del is absent from ClinVar. No reputable source has classified this variant as pathogenic. OncoKB lists the variant as 'Unknown Oncogenic Effect,' which does not constitute a pathogenic classification. Details ▾Hide ▴
BA1 NM_020975.5:c.2434del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Allele frequency does not exceed the BA1 threshold of 1%. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD population databases
Sources
BS1 NM_020975.5:c.2434del is absent from all gnomAD population databases. Allele frequency does not exceed the BS1 threshold of 0.3% for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD population databases
Sources
BS2 No observations in healthy adults are documented for NM_020975.5:c.2434del. The variant is absent from gnomAD population databases, providing no evidence of occurrence in healthy individuals. Details ▾Hide ▴
BS3 No functional studies demonstrating a neutral or benign effect are available for NM_020975.5:c.2434del. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. Details ▾Hide ▴
Still missing
- No functional data available
BS4 No segregation data are available for assessment of lack of segregation with disease. BS4 requires observation of non-segregation in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available
BP2 No data on observation in trans with a known pathogenic variant are available for NM_020975.5:c.2434del. Details ▾Hide ▴
Still missing
- No trans-phase data available
BP4 SpliceAI predicts no splice impact (max delta score = 0.00), but this does not constitute multiple lines of computational evidence suggesting a benign effect. REVEL and BayesDel are unavailable for this non-SNV variant. BP4 requires multiple lines of computational evidence supporting a benign effect, which is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00
- insufficient to meet BP4 threshold
Sources
BP5 No observation of NM_020975.5:c.2434del in a case with an alternate molecular basis for disease has been documented. BP5 requires the variant to be found in a case with a clear alternate genetic cause. Details ▾Hide ▴
Still missing
- No cases with alternate molecular cause available
BP6 NM_020975.5:c.2434del is absent from ClinVar. No reputable source has classified this variant as benign. BP6 requires a reputable source to classify the variant as benign. Details ▾Hide ▴
Not assessed · 1 · no assessment recorded
PM1 The variant occurs at codon 812 within the RET tyrosine kinase domain (aa 724-1016), a well-characterized critical functional domain. The frameshift truncates the kinase domain at codon 868, removing the activation loop and C-terminal tail. PM1 applied at moderate strength at the domain level. Details ▾Hide ▴
Evidence considered
- Frameshift at codon 812 truncates the RET tyrosine kinase domain (aa 724-1016)
- Kinase domain is a critical functional domain well-characterized in the literature
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to different nucleotide changes resulting in the same amino acid substitution. This is a frameshift deletion, not a missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions and stop-loss variants that alter protein length. This is a frameshift variant; PM4 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies to missense variants at the same residue as a known pathogenic missense change. This is a frameshift variant. The PM5 candidates pipeline confirms no same-residue comparator variants are available. Details ▾Hide ▴
Evidence considered
- PM5 candidates pipeline: not_applicable for frameshift variants
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a known mechanism. This is a frameshift variant. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where only truncating variants cause disease. This is a truncating (frameshift) variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a frameshift variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants without predicted splice impact. This is a frameshift variant. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 framework (Richards et al. 2015, PMID:25741868). VCEP-specific frameworks may define PS5, but no RET CSPEC/VCEP is available and the case uses generic ACMG. This is also a frameshift variant, not a missense at a residue with a known pathogenic missense change. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- RET
- Transcript
- NM_020975.5
- Coding (HGVS c.)
- NM_020975.5:c.2434del
- Protein (HGVS p.)
- NP_066124.1:p.(Leu812CysfsTer57)
- GRCh38
- chr10:43119569 TC>T
- GRCh37
- chr10:43615017 TC>T
Gene diagram
Every interpreted variant in RET, mapped onto the exon structure of NM_020975.5. Select a row to find it on the plot.
RETNM_020975.5
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 RET
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele 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
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not available for this non-SNV variant. No in silico evidence supports pathogenicity. PP3 cannot be applied in the absence of multiple lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00 (no splice impact)
- REVEL and BayesDel not applicable for non-SNV variants
Sources
BP4 SpliceAI predicts no splice impact (max delta score = 0.00), but this does not constitute multiple lines of computational evidence suggesting a benign effect. REVEL and BayesDel are unavailable for this non-SNV variant. BP4 requires multiple lines of computational evidence supporting a benign effect, which is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00
- insufficient to meet BP4 threshold
Sources
BP7 N/ABP7 applies to synonymous variants without predicted splice impact. This is a frameshift variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_020975.5%3Ac.2434del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-43615017-TC-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-43119569-TC-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-43119569-TC-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_020975.5%3Ac.2434…
- OncoKB ↗www.oncokb.org/gene/RET/L812Cfs*57
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RET+c.2434del
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.