Variant classification summary

NM_020975.6:c.2689C>T

RET · NP_066124.1:p.(Arg897Ter) · NM_020975.6

GRCh37: chr10:43615610 C>T · GRCh38: chr10:43120162 C>T

Gene: RET Transcript: NM_020975.6

Final call

Pathogenic

PVS1 very strong PM2 moderate PP5 supporting

Variant details

Gene

RET

Transcript

NM_020975.6

Protein

NP_066124.1:p.(Arg897Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_020975.6:c.2689C>T (p.Arg897Ter) is a nonsense variant in exon 15 of 20 in the RET gene. Loss-of-function variants in RET are an established cause of Hirschsprung disease.

2

Nonsense-mediated decay is predicted as the premature termination codon at Arg897 is located >50 nucleotides upstream of the last exon-exon junction. This variant qualifies for PVS1 at very strong strength under the ClinGen SVI PVS1 decision tree (PMC6185798).

3

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, supporting PM2 at moderate strength.

4

ClinVar reports this variant as Pathogenic from two clinical testing laboratories (GeneDx and Labcorp/Invitae), supporting PP5 at supporting strength.

5

Applying the generic ACMG/AMP 2015 final classification combination rules: one very strong criterion (PVS1), one moderate criterion (PM2), and one supporting criterion (PP5) combine to support a Pathogenic classification.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting 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_020975.6:c.2689C>T is a nonsense variant introducing a premature termination codon at p.Arg897Ter in exon 15 of 20. Nonsense-mediated decay is predicted. RET loss-of-function is an established germline disease mechanism for Hirschsprung disease. Under the ClinGen SVI PVS1 decision tree (PMC6185798), this null variant in a gene with confirmed LoF mechanism qualifies for PVS1 at very strong strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to missense variants where a different nucleotide change produces the same amino acid substitution as a known pathogenic variant. This is a nonsense variant introducing a premature termination codon; there is no alternative nucleotide change at this position that produces the same stop codon.
PS2	Not met	No de novo occurrence data are available for this variant in the case materials or literature reviewed.
PS3	Not met	No variant-specific functional studies were identified for NM_020975.6:c.2689C>T (p.Arg897Ter). OncoKB lists this variant as 'Unknown Oncogenic Effect.' The published literature citing this ClinVar entry does not contain experimental functional data for this variant.	oncokb
PS4	Not met	No case-control data comparing the prevalence of this variant in affected individuals versus controls are available. The ClinVar-cited publications (PMID:22174939, PMID:22648184) discuss RET variants in Hirschsprung disease cohorts but do not specifically report NM_020975.6:c.2689C>T (p.Arg897Ter).	PMID:22174939 PMID:22648184
PS5	Not met	PS5 requires multiple reputable sources or expert panel classification with consistent evidence. While ClinVar reports Pathogenic classification from 2 clinical laboratories, both are single-submitter reviews ('criteria provided, single submitter'), and the underlying evidence papers cited do not specifically mention this variant. This does not meet the strong-level threshold for PS5.	clinvar
PM1	Not met	While the variant truncates RET within the tyrosine kinase domain 1 (aa 724-1016), a well-characterized functional domain, this truncation effect is already fully captured by PVS1. Applying PM1 for the same domain loss would constitute double-counting of the same evidence under ACMG/AMP 2015 guidance. The variant does not lie in a statistically significant residue-specific cancer hotspot (cancerhotspots.org).	pvs1_variant_assessment
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating it is not a common benign polymorphism in population databases (allele frequency <0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 applies to variants observed in trans with a pathogenic variant in recessive disorders. RET-associated conditions (Hirschsprung disease, MEN2) are autosomal dominant.
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is a single nucleotide substitution producing a nonsense change.
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue. This variant is a nonsense (stop-gain) change, not a missense variant, and does not meet the semantics of PM5. The automated PM5 candidate search confirmed no classic same-residue comparator is applicable.	pm5_candidates
PM6	Not met	No de novo data are available for this variant; parental testing results have not been provided.
PP1	Not met	No co-segregation data are available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common mechanism of disease. This is a nonsense variant.
PP3	N/A	In silico missense predictors (REVEL, BayesDel) are not designed to assess nonsense variants. SpliceAI predicts no significant splice impact (max delta score = 0.04). The variant's null effect is already captured by PVS1; stacking PP3 would constitute double-counting of the same evidence.	spliceai bayesdel
PP4	Not met	No patient phenotype or family history information has been provided in the case materials for evaluation.
PP5	Met	ClinVar classifies this variant as Pathogenic based on submissions from two clinical testing laboratories (GeneDx and Labcorp/Invitae). While the review status is 'criteria provided, single submitter' and the cited PMIDs do not specifically name this variant, the Pathogenic classification from multiple reputable clinical laboratories is consistent with the predicted impact of a nonsense variant in a gene with established loss-of-function disease mechanism.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1, far below the BA1 threshold of >1% allele frequency in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD, far below the BS1 threshold of >0.3% allele frequency.	gnomad_v2 gnomad_v4
BS2	Not met	No evidence is available that this variant has been observed in healthy adult controls with full penetrance expected.
BS3	Not met	No well-established functional studies demonstrate a benign effect for this variant. No functional data at all were identified for this variant.
BS4	Not met	No non-segregation data are available for this variant.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants are a known cause of disease. This is a truncating (nonsense) variant.
BP2	Not met	No evidence that this variant has been observed in trans with a pathogenic variant in a recessive disorder. RET-associated conditions are autosomal dominant.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions. This variant is a single nucleotide substitution.
BP4	N/A	In silico predictors for benign effect are not designed for nonsense variants. SpliceAI max delta score of 0.04 indicates no significant splice alteration, but the variant's primary effect is through protein truncation, not aberrant splicing.	spliceai
BP5	Not met	No evidence that this variant has been observed in a case with an alternate molecular basis for disease.
BP6	Not met	ClinVar classifies this variant as Pathogenic, not Benign. BP6 is not applicable.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. This is a nonsense (stop-gain) variant.

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