NM_020975.5:c.2434del

RET · NP_066124.1:p.(Leu812CysfsTer57) · NM_020975.5

GRCh37: chr10:43615017 TC>T · GRCh38: chr10:43119569 TC>T

Gene: RET Transcript: NM_020975.5

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

RET

Transcript

NM_020975.5

Protein

NP_066124.1:p.(Leu812CysfsTer57)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 applies to different nucleotide changes resulting in the same amino acid substitution. This is a frameshift deletion, not a missense substitution.
PS2	Not met	No de novo observation has been reported for NM_020975.5:c.2434del. No literature or clinical data document a confirmed de novo occurrence.
PS3	Not met	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.
PS4	Not met	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.
PS5	N/A	PS5 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.
PM1	Not assessed	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame deletions/insertions and stop-loss variants that alter protein length. This is a frameshift variant; PM4 is not applicable.
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not met	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.
PP1	Not met	No segregation data are available for NM_020975.5:c.2434del. PP1 requires evidence of cosegregation with disease in multiple affected family members.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai
PP4	Not met	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.
PP5	Not met	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.	clinvar oncokb
BA1	Not met	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%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.
BS4	Not met	No segregation data are available for assessment of lack of segregation with disease. BS4 requires observation of non-segregation in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. This is a truncating (frameshift) variant.
BP2	Not met	No data on observation in trans with a known pathogenic variant are available for NM_020975.5:c.2434del.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a frameshift variant.
BP4	Not met	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.	spliceai
BP5	Not met	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.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 applies to synonymous variants without predicted splice impact. This is a frameshift variant.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.