RETc.2689C>TPathogenic

Print report

Variant interpretation report

RET c.2689C>T, p.(Arg897Ter)

NM_020975.6:c.2689C>T NP_066124.1:p.(Arg897Ter) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About RET

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 2 Pathogenic
Pipeline record: 10 Jul 2026 · version 7.0.3

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): 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.
PM2 (moderate): 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%).
PP5 (supporting): 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.

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: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PVS1Very strong

PVS1 · very strong

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.

PM2Moderate

PM2 · moderate

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%).

PP5Supporting

PP5 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: 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, PP5 supporting; combination = 1 very strong + 1 moderate + 1 supporting, which maps to 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.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.040 maximum delta

Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

2 reported laboratory submissions

2 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Applied · PP5 → 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

1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV60695393, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 16 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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).

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

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

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.

Met · 3

PVS1 Very strongNM_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. Details ▾Hide ▴

Evidence considered

Nonsense variant p.Arg897Ter in exon 15 of 20 (NM_020975.6). NMD predicted: PTC located >50 nt upstream of the last exon-exon junction.
RET loss-of-function is an established germline disease mechanism
supported by literature linking RET LoF variants to Hirschsprung disease (HSCR).
NM_020975.6 is the MANE Select transcript for RET
exon 15 is present in biologically relevant transcripts.

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

PM2 ModerateThis 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%). Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (exomes).
Absent from gnomAD v4.1 (exomes).
Absent from gnomAD-Canada v1.0 (genomes).

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP5 SupportingClinVar 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. Details ▾Hide ▴

Evidence considered

ClinVar variation ID 405536: Pathogenic classification from 2 clinical laboratories (GeneDx SCV002498866
Labcorp/Invitae SCV000543814).
Both submissions are from clinical testing laboratories with criteria provided.

Sources

clinvar ↗

Not met · 16 · evaluated, threshold not reached

PS2 No de novo occurrence data are available for this variant in the case materials or literature reviewed. Details ▾Hide ▴

Still missing

De novo status has not been assessed for this variant.

PS3 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. Details ▾Hide ▴

Evidence considered

OncoKB classification: Unknown Oncogenic Effect
no curated functional data for p.Arg897Ter.
No functional studies in the literature specifically test this variant or a systematically characterized range that includes position 897.

Still missing

No functional characterization of this variant or a systematic tiling/saturation screen spanning residue 897 has been published.

Sources

oncokb ↗

PS4 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). Details ▾Hide ▴

Evidence considered

PMID:22174939: RET mutational spectrum in 601 Chinese HSCR patients
this specific variant is not reported in the publication.
PMID:22648184: RET variants in HSCR and enteric neural crest cell gene study
this specific variant is not reported.

Still missing

No case-control or cohort data quantifying enrichment of this variant in affected individuals.

Sources

PMID:22174939 ↗PMID:22648184 ↗

PM1 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). Details ▾Hide ▴

Evidence considered

Variant truncates RET at position 897 within tyrosine kinase domain 1
removing C-terminal kinase function.
Not located in a statistically significant residue-specific hotspot per cancerhotspots.org.
Domain-level evidence for truncation is already accounted for by PVS1.

Sources

pvs1_variant_assessment

PM6 No de novo data are available for this variant; parental testing results have not been provided. Details ▾Hide ▴

Still missing

Parental genotypes not available to assess de novo status.

PP1 No co-segregation data are available for this variant. Details ▾Hide ▴

Still missing

No family segregation data available.

PP4 No patient phenotype or family history information has been provided in the case materials for evaluation. Details ▾Hide ▴

Still missing

Patient phenotype and family history not available for assessment.

BA1 The variant is absent from gnomAD v2.1 and v4.1, far below the BA1 threshold of >1% allele frequency in population databases. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (AF = 0).
Absent from gnomAD v4.1 (AF = 0).

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 The variant is absent from gnomAD, far below the BS1 threshold of >0.3% allele frequency. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (AF = 0).
Absent from gnomAD v4.1 (AF = 0).

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 No evidence is available that this variant has been observed in healthy adult controls with full penetrance expected. Details ▾Hide ▴

Still missing

No control population data beyond gnomAD available.

BS3 No well-established functional studies demonstrate a benign effect for this variant. No functional data at all were identified for this variant. Details ▾Hide ▴

Still missing

No functional studies available for this variant.

BS4 No non-segregation data are available for this variant. Details ▾Hide ▴

Still missing

No family segregation data available to evaluate non-segregation.

BP2 No evidence that this variant has been observed in trans with a pathogenic variant in a recessive disorder. RET-associated conditions are autosomal dominant. Details ▾Hide ▴

No further detail was recorded.

BP5 No evidence that this variant has been observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴

No further detail was recorded.

BP6 ClinVar classifies this variant as Pathogenic, not Benign. BP6 is not applicable. Details ▾Hide ▴

Evidence considered

ClinVar reports Pathogenic classification
BP6 requires a reputable source reporting the variant as benign.

Sources

clinvar ↗

PS5 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. Details ▾Hide ▴

Evidence considered

ClinVar variation ID 405536: Pathogenic
2 submitters (GeneDx
Labcorp/Invitae)
review status 'criteria provided
single submitter'.
Cited PMIDs (22174939
22648184
28492532) do not mention this variant specifically.

Sources

clinvar ↗

Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 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. Details ▾Hide ▴

No further detail was recorded.

PM3 N/APM3 applies to variants observed in trans with a pathogenic variant in recessive disorders. RET-associated conditions (Hirschsprung disease, MEN2) are autosomal dominant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 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. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 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. Details ▾Hide ▴

Evidence considered

PM5 candidate analysis returned 'not_applicable': nonsense variants are not eligible for classic PM5
which requires a different pathogenic missense at the same codon.

Sources

pm5_candidates

PP2 N/APP2 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. Details ▾Hide ▴

No further detail was recorded.

PP3 N/AIn 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score: 0.04 (no significant splice alteration predicted).
BayesDel score: 0.66 (not applicable to nonsense variant assessment).
REVEL: not available for this variant.

Sources

spliceai ↗bayesdel

BP1 N/ABP1 applies to missense variants in genes where only truncating variants are a known cause of disease. This is a truncating (nonsense) variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions. This variant is a single nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

BP4 N/AIn 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta: 0.04 (no splicing impact predicted).
In silico tools not designed for nonsense variant benign-effect assessment.

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This is a nonsense (stop-gain) variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: RET
Transcript: NM_020975.6
Coding (HGVS c.): NM_020975.6:c.2689C>T
Protein (HGVS p.): NP_066124.1:p.(Arg897Ter)
GRCh38: chr10:43120162 C>T
GRCh37: chr10:43615610 C>T
ClinVar: 1798084, 1796396, 405536
COSMIC: COSV60695393

Gene diagram

Every interpreted variant in RET, mapped onto the exon structure of NM_020975.6. Select a row to find it on the plot.

RETNM_020975.6

Fetching transcript structure from UCSC…

Exons

—

Transcript span

—

Strand

—

Variants mapped

—

Source

UCSC ncbiRefSeqCurated

All variants in RET — 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

SpliceAI acceptor lossat +249 bp

0.020

SpliceAI acceptor gainat -452 bp

0.000

SpliceAI donor lossat +41 bp

0.000

SpliceAI donor gainat +84 bp

0.040

Pangolin splice lossmagnitude shown

-0.070

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: 0.660

How the predictions were used

Evidence considered

SpliceAI max delta score: 0.04 (no significant splice alteration predicted).
BayesDel score: 0.66 (not applicable to nonsense variant assessment).
REVEL: not available for this variant.

Sources

spliceai ↗bayesdel

Evidence considered

SpliceAI max delta: 0.04 (no splicing impact predicted).
In silico tools not designed for nonsense variant benign-effect assessment.

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This is a nonsense (stop-gain) variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.66.

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

Guidelines for diagnosis and therapy of MEN type 1 and type 2.

Brandi ML et al. · 2001

Consensus guidelines for diagnosis and therapy of MEN type 1 and type 2. Discusses RET as the causative gene for MEN2 with gain-of-function mutations. No mention of specific RET variants including NM_020975.6:c.2689C>T.
Does not name this variant
PMID 11739416 ↗
RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients.

So MT et al. · 2011

Reports RET coding sequence variant spectrum in 601 Chinese Hirschsprung disease patients. NM_020975.6:c.2689C>T (p.Arg897Ter) was not identified in this publication.
Does not name this variant
PMID 22174939 ↗
Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation.

Carter TC et al. · 2012

Evaluates RET coding and splice-site variants in a population-based Hirschsprung disease case group and tests associations with candidate genes. NM_020975.6:c.2689C>T (p.Arg897Ter) was not identified in this publication.
Does not name this variant
PMID 22648184 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.

Trepanier A et al. · 2004

National Society of Genetic Counselors practice recommendations for cancer genetic risk assessment and counseling. Lists MEN2/RET in a table of hereditary cancer syndromes but does not discuss specific RET variants. NM_020975.6:c.2689C>T was not identified.
Does not name this variant
PMID 15604628 ↗
Multiple Endocrine Neoplasia Type 2.

Adam MP et al. · 1993

GeneReviews entry on Multiple Endocrine Neoplasia Type 2. Summarizes RET-associated MEN2 syndromes. No variant-level discussion of NM_020975.6:c.2689C>T was identified in available metadata.
Does not name this variant
PMID 20301434 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.

PDQ Cancer Genetics Editorial Board · 2002

PDQ cancer genetics risk assessment and counseling summary. Provides general cancer genetics guidance without variant-specific RET information. NM_020975.6:c.2689C>T was not identified in available metadata.
Does not name this variant
PMID 26389258 ↗
Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®): Health Professional Version.

PDQ Cancer Genetics Editorial Board · 2002

PDQ summary on genetics of endocrine and neuroendocrine neoplasias. Discusses RET in the context of MEN2 syndromes at the gene level. NM_020975.6:c.2689C>T was not identified in available metadata.
Does not name this variant
PMID 26389271 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K et al. · 2017

Sherloc refinement of ACMG-AMP variant classification criteria. A methodological paper describing variant interpretation framework. Does not discuss specific RET variants including NM_020975.6:c.2689C>T.
Does not name this variant
PMID 28492532 ↗

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 0.040 Open source ↗

ClinVar 2 Pathogenic 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

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 has been reported in ClinVar as Pathogenic (2 clinical laboratories). (ClinVarID = 405536)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.66.

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 previously been reported in somatic cancers (COSMIC; COSV60695393, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.