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.
Words with a dotted underline have a short definition. Hover or tap them.
About RET
RET encodes a receptor tyrosine kinase that, when activated by GDNF-family ligands, triggers signaling pathways involved in cell growth, differentiation, migration, and survival, and is essential for development of the nervous system and neural crest-derived tissues. Germline changes in RET cause Hirschsprung disease, congenital central hypoventilation syndrome, and the inherited cancer syndromes multiple endocrine neoplasia type 2A and 2B and familial medullary thyroid carcinoma. In cancer, RET is a proto-oncogene that can be turned on by point mutations or gene rearrangements, driving malignancies such as medullary and papillary thyroid carcinoma, lung adenocarcinoma, and chronic myelomonocytic leukemia, and abnormal RET activity has also been linked to invasion and metastasis in pancreatic cancer and to endocrine therapy resistance in breast cancer.
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.
Met (Supporting): extremely rare, 3/1,612,934 alleles (0.00019%) in gnomAD v4.1 with 0 homozygotes, far below the <0.1% threshold.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Met (Supporting): REVEL 0.262 falls at or below the <=0.290 BP4_Supporting cutoff.
Recorded classification: Uncertain significance
VUS: only PM2 (Supporting, pathogenic) and BP4 (Supporting, benign) are met, satisfying no ACMG/AMP 2015 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
3 / 1,612,934 alleles
gnomAD v4.1: 3 / 1,612,934 alleles. Recorded AF 1.85996e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.0213e-06; MAF= 0.00040%, 1/248676 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89939e-05; MAF= 0.00290%, 1/34490 alleles, homozygotes = 0).
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RET, a receptor tyrosine kinase, is altered by mutation in medullary thyroid cancers and by chromosomal rearrangement in lung cancers, papillary thyro
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 6 not met · 16 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No governing ClinGen RET VCEP specification is present for this case; generic ACMG/AMP guidance (PMID:25741868) applies by default.
No functional/in-vitro assay evidence for NM_020975.5:c.2486G>A was located anywhere in the case evidence bundle (evidence.json, prefetch.json, literature_pass.json, source_registry.json) or in the full-text of the ClinVar-cited publications reviewed, all of which are practice guidelines rather than primary functional studies.
PS3 and BS3 are therefore both not_assessed pending identification of a variant-specific functional study.
No RET-specific CSPEC/VCEP framework was available, so generic ACMG/AMP concepts were used only where applicable.
The exact variant is RET NM_020975.5:c.2486G>A, p.Ser829Asn.
No exact-variant expert-panel ClinVar classification exists; therefore PP5 and BP6 are not met.
General RET/MEN2 phenotype descriptions and non-expert ClinVar assertions were not treated as exact-variant PS4, PP4, BP5, PP5, or BP6 evidence.
Variant is a missense substitution (NM_020975.5:c.2486G>A, NP_066124.1:p.(Ser829Asn)); RET has no gene-specific VCEP cspec in this case bundle, so generic ACMG calibration with published REVEL thresholds (PMID 36413997) governs the missense in-silico path.
REVEL = 0.262 meets the BP4_Supporting cutoff (<=0.290) and is well below the PP3_Supporting cutoff (>=0.644), so BP4 (Supporting) is met and PP3 is not met.
SpliceAI max delta = 0.011 shows no predicted splicing impact, so the splice-impact path does not independently trigger PP3 and is not in conflict with the benign missense in-silico signal.
BayesDel score exists but is excluded from both PP3 and BP4 per pipeline policy: no verified published threshold/PMID is available for BayesDel.
No BP7 assessment applicable: variant is missense, not synonymous.
No ClinGen CSPEC/VCEP or local RET-specific framework was retrieved; generic ACMG/AMP 2015 rules therefore govern this group.
BA1 and BS1 are not met: the maximum observed raw subpopulation AF is 0.00290%, far below the operational thresholds of >1% and >0.3%, respectively.
BS2 is not met: rare unphenotyped heterozygous carriers in gnomAD, with no homozygotes, do not establish healthy-adult status or full penetrance.
PM2 is met at supporting strength: the variant is ultra-rare across gnomAD v2.1 and v4.1 and absent from gnomAD-Canada, with 0 homozygotes and maximum observed AF 0.00290%, below the <0.1% operational threshold.
No criteria match.
Met · 2
PM2SupportingMet (Supporting): extremely rare, 3/1,612,934 alleles (0.00019%) in gnomAD v4.1 with 0 homozygotes, far below the <0.1% threshold.
Details ▾Hide ▴
Reasoning
The variant is extremely rare in population databases. gnomAD v4.1 reports 3/1,612,934 alleles (AF 1.85996e-06; 0.00019%) with 0 homozygotes and grpmax FAF 2.8e-07; gnomAD v2.1 reports 1/248,676 alleles (AF 4.0213e-06; 0.00040%) with 0 homozygotes. The highest ancestry-specific frequencies remain only 0.00290% in gnomAD v2.1 and 0.00167% in gnomAD v4.1, below the operational generic PM2 threshold of <0.1%. gnomAD-Canada v1.0 is absent.
Rule
Generic ACMG/AMP 2015 (PMID:25741868): PM2 applies to an absent or extremely rare variant in population databases; operational non-VCEP threshold used here is <0.1%, applied at supporting strength.
Evidence considered
gnomAD v2.1: 1/248,676 alleles, AF 4.0213e-06 (0.00040%), 0 homozygotes; highest Admixed American AF 2.89939e-05 (0.00290%).
gnomAD v4.1: 3/1,612,934 alleles, AF 1.85996e-06 (0.00019%), 0 homozygotes; highest Admixed American AF 1.66594e-05 (0.00167%); grpmax FAF 2.8e-07.
BP4SupportingMet (Supporting): REVEL 0.262 falls at or below the <=0.290 BP4_Supporting cutoff.
Details ▾Hide ▴
Reasoning
No governing VCEP/gene-specific cspec was found for RET in this case bundle, so generic ACMG in-silico calibration applies. REVEL score = 0.262 falls at/below the ClinGen SVI-recommended BP4_Supporting cutoff (REVEL <=0.290) per the published REVEL calibration (Pejaver et al., PMID 36413997), supporting a benign computational prediction at supporting strength (not moderate, since 0.262 is above the BP4_Moderate cutoff of <=0.183). SpliceAI max delta score = 0.011 is far below any splice-disruption threshold, consistent with no predicted splicing impact and not contradicting the benign missense in-silico signal. BayesDel score is available but excluded because no verified published threshold/PMID for BayesDel exists in this pipeline; the classification relies on REVEL alone as the calibrated missense predictor.
Rule
Generic ACMG/AMP (no gene-specific VCEP cspec available for RET in this case); REVEL calibrated thresholds per Pejaver et al. (PMID 36413997); BP4 applied at Supporting strength only (score does not reach the Moderate cutoff).
Evidence considered
REVEL score = 0.262 (source: local REVEL v1.3 predictor lookup), at/below the ClinGen SVI BP4_Supporting cutoff of <=0.290 for REVEL (Pejaver et al., PMID 36413997), consistent with a benign computational prediction at supporting strength.
SpliceAI predicts no significant splice impact (max delta score = 0.011; DS_AG=0.011, DS_AL=0.003, DS_DG=0.0, DS_DL=0.0), consistent with no splice-based pathogenic signal counteracting the benign in-silico missense prediction.
Still missing
BayesDel score (-0.304934) not used because no verified/citable calibration threshold is available for this pipeline.
PP3Not met: REVEL 0.262 is below the >=0.644 PP3_Supporting threshold.
Details ▾Hide ▴
Reasoning
No governing VCEP/gene-specific cspec was found for RET in this case bundle (cspec.found=false, generic_acmg framework_mode), so generic ACMG in-silico calibration applies. This is a missense substitution (NP_066124.1:p.(Ser829Asn)); the missense in-silico path governs. REVEL score = 0.262, well below the ClinGen SVI-recommended PP3_Supporting threshold (REVEL >=0.644), so REVEL does not support a pathogenic computational prediction. SpliceAI max delta score = 0.011, far below any splice-impact threshold (typically 0.2), so no splice-altering effect is predicted and the splice-impact path does not trigger PP3 either. BayesDel score (-0.304934) is available but this pipeline has no verified published threshold/PMID for BayesDel and per policy is treated as not_available/insufficiently calibrated, so it is not used to support or refute PP3. Overall, no calibrated computational tool supports a deleterious/splice-disrupting prediction for this variant.
Rule
Generic ACMG/AMP (no gene-specific VCEP cspec available for RET in this case); REVEL calibrated thresholds per Pejaver et al. (PMID 36413997); SpliceAI screened as secondary splice-impact check for this missense variant.
Evidence considered
REVEL score = 0.262 (source: local REVEL v1.3 predictor lookup), below the ClinGen SVI PP3_Supporting cutoff of >=0.644 established for REVEL calibration (Pejaver et al., PMID 36413997).
SpliceAI predicts no significant splice impact for this variant: DS_AG=0.011, DS_AL=0.003, DS_DG=0.0, DS_DL=0.0, max delta score=0.011 -- well under typical splice-impact thresholds, so no splice-disruption evidence supports PP3.
Still missing
No BayesDel-calibrated threshold with a citable publication is available to this pipeline; BayesDel score exists but cannot be used for PP3.
PP5Not met: ClinVar classifies this variant as uncertain significance with no expert-panel submission.
Details ▾Hide ▴
Reasoning
The exact ClinVar record has no expert-panel submission and is classified as uncertain significance by three single-submitter clinical laboratories. No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present; ordinary submissions, aggregate labels, and non-expert assertions are excluded from PP5.
Rule
Apply PP5 only when the exact variant has a ClinVar expert-panel Pathogenic or Likely pathogenic classification; do not use ordinary laboratory submissions or aggregate ClinVar labels.
Evidence considered
ClinVar variation 1791991 matches NM_020975.5:c.2486G>A (p.Ser829Asn), has three submissions, zero expert-panel submissions, and an aggregate classification of uncertain significance.
The ClinVar submissions are all single-submitter laboratory assertions and none is an expert-panel Pathogenic or Likely pathogenic classification.
BA1Not met: highest population frequency 0.00290% is far below the >1% BA1 threshold.
Details ▾Hide ▴
Reasoning
No population frequency approaches a stand-alone benign threshold. The maximum observed allele frequency is 2.89939e-05 (0.00290%) in the Admixed American population in gnomAD v2.1 and 1.66594e-05 (0.00167%) in gnomAD v4.1; total frequencies are 4.0213e-06 and 1.85996e-06, respectively. These values are far below the operational generic non-VCEP BA1 threshold of >1% and the original ACMG/AMP stand-alone threshold of >5%.
Rule
Generic ACMG/AMP 2015 (PMID:25741868); operational non-VCEP BA1 threshold used here is allele frequency >1% in a large, diverse population database; original stand-alone ACMG/AMP threshold is >5%.
Evidence considered
gnomAD v2.1: total AF 4.0213e-06 (1/248,676 alleles); highest subpopulation AF 2.89939e-05 (1/34,490 Admixed American alleles); 0 homozygotes.
gnomAD v4.1: total AF 1.85996e-06 (3/1,612,934 alleles); highest subpopulation AF 1.66594e-05 (1/60,026 Admixed American alleles); grpmax FAF 2.8e-07; 0 homozygotes.
BS1Not met: highest subpopulation frequency 0.00290% is far below the >0.3% BS1 threshold.
Details ▾Hide ▴
Reasoning
The observed frequency is not greater than expected for a rare autosomal-dominant RET hereditary cancer syndrome. The highest raw subpopulation frequency is only 0.00290% in gnomAD v2.1 and 0.00167% in gnomAD v4.1, both far below the operational generic non-VCEP BS1 threshold of >0.3%. The small frequency difference between ancestry groups is a sampling/denominator artifact from one allele in each reported highest-frequency subgroup, not evidence of excess disease-compatible frequency.
Rule
Generic ACMG/AMP 2015 (PMID:25741868); BS1 requires an allele frequency greater than expected for the disorder, with the operational non-VCEP threshold used here >0.3% in gnomAD.
Evidence considered
gnomAD v2.1: total AF 4.0213e-06; highest subpopulation AF 2.89939e-05 (0.00290%) in Admixed American; 0 homozygotes.
gnomAD v4.1: total AF 1.85996e-06; highest subpopulation AF 1.66594e-05 (0.00167%) in Admixed American; grpmax FAF 2.8e-07; 0 homozygotes.
The observed maximum frequency is approximately 100-fold below 0.3% even before accounting for RET disease prevalence and penetrance.
Still missing
No RET-specific disease-prevalence calculation or penetrance-adjusted maximum credible allele frequency was available in the case bundle; this does not affect the call because all observed frequencies are orders of magnitude below the operational BS1 threshold.
BS2Not met: no healthy-adult carriers documented, only rare heterozygous alleles with no phenotype data.
Details ▾Hide ▴
Reasoning
No qualifying healthy-adult observation was identified. gnomAD v2.1 and v4.1 report only rare heterozygous alleles and no homozygotes, but provide no phenotype, age, or confirmation that carriers are unaffected adults. The absent gnomAD-Canada record adds no healthy-control observation. For an autosomal-dominant RET disorder with age-dependent penetrance, unphenotyped population carriers cannot establish BS2.
Rule
Generic ACMG/AMP 2015 (PMID:25741868): BS2 requires observation in a healthy adult for a disorder with full penetrance expected at an early age; unphenotyped gnomAD carriers do not meet this requirement.
Evidence considered
gnomAD v2.1: 1 observed allele and 0 homozygotes; no phenotype or age information for the carrier.
gnomAD v4.1: 3 observed alleles and 0 homozygotes; no phenotype or age information for carriers.
gnomAD-Canada v1.0: absent; no healthy-control observation.
Still missing
Phenotyped unaffected-adult carrier data, including age and clinical status, are unavailable; therefore the population records cannot satisfy the healthy-adult/full-penetrance requirement for BS2.
BP6Not met: no expert-panel benign classification; ClinVar record is uncertain significance from three laboratories.
Details ▾Hide ▴
Reasoning
The exact ClinVar record has no expert-panel submission and is classified as uncertain significance by three single-submitter clinical laboratories. No exact-variant ClinVar expert-panel Benign or Likely benign classification is present; ordinary submissions, aggregate labels, and non-expert assertions are excluded from BP6.
Rule
Apply BP6 only when the exact variant has a ClinVar expert-panel Benign or Likely benign classification; do not use ordinary laboratory submissions or aggregate ClinVar labels.
Evidence considered
ClinVar variation 1791991 matches NM_020975.5:c.2486G>A (p.Ser829Asn), has three submissions, zero expert-panel submissions, and an aggregate classification of uncertain significance.
The ClinVar submissions are all single-submitter laboratory assertions and none is an expert-panel Benign or Likely benign classification.
PS1Not assessed: insufficient evidence was available to compare this variant against an established pathogenic change at the same residue.
Details ▾Hide ▴
Reasoning
PS1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: evidence_refs must contain only source_registry keys
attempt 2: evidence_refs must contain only source_registry keys
attempt 3: evidence_refs must contain only source_registry keys
PS2Not assessed: no proband-level parental genotypes or de novo confirmation for p.Ser829Asn were available.
Details ▾Hide ▴
Reasoning
No case-specific evidence documents that NM_020975.5:c.2486G>A (p.Ser829Asn) is de novo in the proband. The evidence bundle contains no proband-level parental genotypes, maternity/paternity confirmation, or parental phenotype information. General RET literature describing de novo mutations is not sufficient to establish PS2 for this variant.
Rule
Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed where applicable; case-specific parental testing is required.
Evidence considered
The consolidated case-evidence bundle identifies the variant as NM_020975.5:c.2486G>A (NP_066124.1:p.Ser829Asn) in RET.
The bundle reports no applicable RET ClinGen CSPEC/VCEP framework and provides no proband-level parental testing or de novo documentation.
The general ACMG/AMP framework was reviewed, but no case-specific evidence meeting PS2 was available.
Still missing
Proband genotype confirmation
Both parental genotype results for the exact variant
Maternity/paternity confirmation or equivalent
Parental clinical phenotypes and relevant age-related evaluation
PS3Not assessed: no functional assay data (kinase activation, transformation, or cell-based) for p.Ser829Asn were available.
Details ▾Hide ▴
Reasoning
No RET-specific ClinGen VCEP specification was found for this case (cspec.found=false, vcep_materials.json note='no cspec url available'), so generic ACMG/AMP applies. The consolidated evidence bundle contains no functional/in-vitro assay data for NM_020975.5:c.2486G>A (p.Ser829Asn): no kinase activation, autophosphorylation, transformation, or cell-based reporter assay results are present in evidence.json, prefetch.json, literature_pass.json, or the ClinVar-linked publications. The retrieved ClinVar-cited papers (PMID:25741868, PMID:25394175, PMID:25810047) are all guideline/consensus documents, not primary functional studies, and none discuss a validated functional assay for this specific variant.
Still missing
No published functional/biochemical assay (e.g. kinase activity, transformation, autophosphorylation) identified for p.Ser829Asn
No RET-specific VCEP functional assay specification available to calibrate assay validity or strength
PS4Not assessed: no case series or affected individuals carrying this exact variant were identified.
Details ▾Hide ▴
Reasoning
No patient-level case series, case-control enrichment analysis, or sufficiently documented affected individuals carrying the exact RET NM_020975.5:c.2486G>A (p.Ser829Asn) variant was identified in the supplied evidence bundle. General RET/MEN2 disease prevalence information cannot establish PS4 for this exact variant.
Rule
PS4 requires statistically significant enrichment of the exact variant in affected individuals compared with controls, or an applicable specified case-count rule.
Evidence considered
The supplied literature triage contains only general RET/MEN2 guidelines and does not provide exact-variant case counts or case-control data.
The exact variant is reported in ClinVar only as uncertain significance from three non-expert laboratory submissions; this is not case-control evidence.
Still missing
Exact-variant affected-case counts and an appropriate case-control comparator are unavailable.
No statistically supported enrichment estimate or validated VCEP threshold is available.
PM1Not assessed: insufficient evidence was available to determine whether p.Ser829Asn lies in a mutational hotspot or critical domain.
Details ▾Hide ▴
Reasoning
PM1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: evidence_refs must contain only source_registry keys
attempt 2: evidence_refs must contain only source_registry keys
attempt 3: evidence_refs must contain only source_registry keys
PM3Not assessed: no observation of this variant in trans with a known pathogenic RET variant was available.
Details ▾Hide ▴
Reasoning
No applicable RET-specific VCEP/CSPEC framework was retrieved, so the generic ACMG/AMP PM3 definition was used. The case bundle contains no affected-proband observations documenting NM_020975.5:c.2486G>A in trans with a known pathogenic RET variant, and provides no phase, parental testing, or inheritance data. Therefore PM3 cannot be assessed.
Rule
Generic ACMG/AMP PM3: moderate evidence when a variant is identified in trans with a pathogenic variant in a recessive disorder; multiple observations may support upgrading. Case-specific phase and affected-proband evidence are required.
Evidence considered
The consolidated case-evidence bundle identifies RET and the missense variant NP_066124.1:p.(Ser829Asn), but contains no family, proband, phase, cis/trans, or co-occurring pathogenic-variant observation usable for PM3.
The generic ACMG/AMP framework defines PM3 using a variant in trans with a pathogenic variant in a recessive disorder; no such case-specific observation is present here.
Still missing
Affected-proband observations involving NM_020975.5:c.2486G>A are not available.
No known pathogenic RET variant in the same individual is documented.
No parental or molecular phasing establishes the variant in trans with a pathogenic RET variant.
The relevant inheritance/disease model for this observation is not documented in the case evidence.
PM5Not assessed: insufficient evidence was available to compare p.Ser829Asn with a previously established pathogenic missense at the same codon.
Details ▾Hide ▴
Reasoning
PM5 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: evidence_refs must contain only source_registry keys
attempt 2: evidence_refs must contain only source_registry keys
attempt 3: evidence_refs must contain only source_registry keys
PM6Not assessed: no presumed de novo occurrence without confirmed parental testing was documented.
Details ▾Hide ▴
Reasoning
No case-specific evidence documents a presumed de novo occurrence of NM_020975.5:c.2486G>A (p.Ser829Asn) without confirmed parental testing. General RET reports of de novo mutations, including gene-level statements in MEN2 literature, cannot substitute for evidence about this proband and this exact variant.
Rule
Generic ACMG/AMP PM6: presumed de novo occurrence when maternity and paternity are not confirmed; the occurrence must still be documented for the exact variant and proband.
Evidence considered
The literature packet contains no exact-variant segregation or de novo report for NM_020975.5:c.2486G>A.
The consolidated bundle contains no parental testing results for this case.
The general ACMG/AMP framework was reviewed, but no case-specific evidence meeting PM6 was available.
Still missing
A case report or cohort report describing this exact variant in the proband
Parental genotype information, even if incompletely documented
Evidence that the variant was absent from tested parents
Clinical phenotype and family-history details supporting a de novo interpretation
PP1Not assessed: no affected relatives or family segregation data were available.
Details ▾Hide ▴
Reasoning
No affected relatives, informative meioses, or family segregation data are provided for NM_020975.5:c.2486G>A (p.Ser829Asn). The available evidence is limited to variant normalization, population data, computational data, and ClinVar metadata; none establishes segregation with disease in this family.
Rule
Generic ACMG/AMP PP1: co-segregation with disease in multiple affected family members; strength depends on the number and informativeness of meioses and phenotype specificity.
Evidence considered
The consolidated case-evidence bundle contains no pedigree, affected-relative testing, family genotypes, or informative meioses.
ClinVar classifications and generic RET disease descriptions do not constitute family-specific segregation evidence.
The general ACMG/AMP framework was reviewed, but no case-specific evidence meeting PP1 was available.
Still missing
Pedigree with phenotype information
Genotypes of affected relatives
Genotypes and phenotypes of unaffected relatives
Number of informative meioses and segregation phase
Phenotype concordance and age-related penetrance assessment
PP2Not assessed: insufficient evidence was available to evaluate this variant in a gene with low rates of benign missense variation.
Details ▾Hide ▴
Reasoning
PP2 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: evidence_refs must contain only source_registry keys
attempt 2: evidence_refs must contain only source_registry keys
attempt 3: evidence_refs must contain only source_registry keys
PP4Not assessed: no patient-specific phenotype or diagnostic findings for this variant carrier were available.
Details ▾Hide ▴
Reasoning
The bundle does not provide patient-specific phenotype or diagnostic findings for an individual carrying the exact variant. General descriptions of MEN2/medullary thyroid carcinoma phenotype are insufficient to establish a highly specific phenotype in this variant carrier.
Rule
PP4 requires a highly specific phenotype or family history consistent with the disease for the exact variant carrier; gene-level disease descriptions alone are insufficient.
Evidence considered
The reviewed ATA guideline describes phenotype associations for specific RET mutations in hereditary MTC, but it does not report NM_020975.5:c.2486G>A/p.Ser829Asn or provide phenotype data for a carrier of this exact variant.
The case bundle reports no exact-variant patient phenotype; therefore a general RET/MEN2 phenotype cannot be attributed to this variant.
Still missing
Variant-carrier clinical phenotype, diagnostic findings, and phenotype-to-disease specificity are unavailable.
No RET-specific PP4 specification was available because no RET CSPEC/VCEP framework was found.
BS3Not assessed: no functional assay data demonstrating normal protein function were available.
Details ▾Hide ▴
Reasoning
No RET-specific ClinGen VCEP specification was found for this case (cspec.found=false), so generic ACMG/AMP applies. The consolidated evidence bundle contains no functional/in-vitro assay data showing normal/wild-type function for NM_020975.5:c.2486G>A (p.Ser829Asn); no such data appears in evidence.json, prefetch.json, literature_pass.json, or the retrieved publications, which are guideline documents rather than primary functional studies.
Still missing
No published functional assay demonstrating normal RET function for p.Ser829Asn was identified
No RET-specific VCEP functional assay specification available to calibrate assay validity or strength
BS4Not assessed: no family data showing failure of this variant to segregate with disease were available.
Details ▾Hide ▴
Reasoning
No family data show that NM_020975.5:c.2486G>A (p.Ser829Asn) fails to segregate with disease. There are no reported unaffected carriers, no tested relatives with discordant phenotypes, and no family-level non-segregation analysis.
Rule
Generic ACMG/AMP BS4: lack of segregation in affected members of a family; requires informative family testing and phenotype assessment, with consideration of reduced penetrance and phenocopies.
Evidence considered
The consolidated case-evidence bundle contains no unaffected-carrier observations or other family non-segregation data.
Population observations in gnomAD are not family segregation evidence and cannot establish BS4.
The general ACMG/AMP framework was reviewed, but no case-specific evidence meeting BS4 was available.
Still missing
Genotypes of unaffected relatives
Phenotype and age information for tested relatives
Evidence of variant presence in clinically unaffected relatives beyond expected age of onset
Assessment of whether any apparent non-segregation is explained by reduced penetrance or phenocopy
BP1Not assessed: insufficient evidence was available to evaluate presence of a known benign variant in trans.
Details ▾Hide ▴
Reasoning
BP1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: evidence_refs must contain only source_registry keys
attempt 2: evidence_refs must contain only source_registry keys
attempt 3: evidence_refs must contain only source_registry keys
BP2Not assessed: no second RET variant or cis/trans phase data were available.
Details ▾Hide ▴
Reasoning
No applicable RET-specific VCEP/CSPEC framework was retrieved, so the generic ACMG/AMP BP2 definition was used. The case bundle contains no documented second variant in RET, no cis phase result, and no observation of the target variant in trans with a pathogenic variant in a dominant disease model. Therefore BP2 cannot be assessed.
Rule
Generic ACMG/AMP BP2: supporting benign evidence when a second variant is found in cis with the target variant, or when the target variant is in trans with a pathogenic variant in a dominant disease model; phase and disease-model context are required.
Evidence considered
The consolidated case-evidence bundle does not document a second RET variant, cis/trans phase, affected-proband allelic observation, or inheritance result for NM_020975.5:c.2486G>A.
The generic ACMG/AMP framework describes BP2 for a second variant found in cis with the target variant, or for the target variant found in trans with a pathogenic variant in a dominant disease model; neither observation is present here.
Still missing
No second RET variant is documented in the case evidence.
No cis phase result is available.
No trans observation with a pathogenic variant relevant to a dominant disease model is available.
No affected-proband or inheritance context is available to determine whether BP2 applies.
BP5Not assessed: no evidence that this variant occurred with a confirmed alternative molecular cause of disease.
Details ▾Hide ▴
Reasoning
No reliable evidence shows that the exact variant was identified in a patient with a confirmed alternative molecular cause of the phenotype. General disease or gene-level information cannot establish BP5.
Rule
BP5 requires the exact variant in an affected individual with a confirmed alternative molecular cause explaining the phenotype.
Evidence considered
The supplied case bundle contains no exact-variant report documenting an alternative molecular cause that would explain the relevant phenotype.
Still missing
A documented patient with the exact variant and a confirmed alternative molecular explanation for the phenotype is unavailable.
Not applicable · 4· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: this is a missense variant (p.Ser829Asn), so no null-variant mechanism such as nonsense-mediated decay applies.
Details ▾Hide ▴
Reasoning
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_020975.5:c.2486G>A in RET is a missense substitution predicted to produce NP_066124.1:p.(Ser829Asn). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
PM4N/ANot applicable: missense substitution, so no protein length change occurs.
Details ▾Hide ▴
Reasoning
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_020975.5:c.2486G>A in RET is a missense substitution predicted to produce NP_066124.1:p.(Ser829Asn). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
BP3N/ANot applicable: missense substitution, not an in-frame indel in a repetitive region.
Details ▾Hide ▴
Reasoning
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_020975.5:c.2486G>A in RET is a missense substitution predicted to produce NP_066124.1:p.(Ser829Asn). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
BP7N/ANot applicable: missense substitution, not a synonymous variant.
Details ▾Hide ▴
Reasoning
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_020975.5:c.2486G>A in RET is a missense substitution predicted to produce NP_066124.1:p.(Ser829Asn). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
Rule
deterministic_prefilter: requires_synonymous
Evidence considered
Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
Identifiers
Gene
RET
Transcript
NM_020975.5
Coding (HGVS c.)
NM_020975.5:c.2486G>A
Protein (HGVS p.)
NP_066124.1:p.(Ser829Asn)
GRCh38
chr10:43119624 G>A
GRCh37
chr10:43615072 G>A
Location and type
Exon 14 · missense
ClinVar
3432269, 1791991
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
—
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.
AF 1.9e-06 · 3 / 1,612,934 alleles · 0 hom · FAF 2.8e-07
Admixed American1 / 60,026
1.7e-05
European (non-Finnish)2 / 1,179,944
1.7e-06
0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 248,676 alleles · 0 hom
Admixed American1 / 34,490
2.9e-05
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85996e-06; MAF= 0.00019%, 3/1612934 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66594e-05; MAF= 0.00167%, 1/60026 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.0213e-06; MAF= 0.00040%, 1/248676 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89939e-05; MAF= 0.00290%, 1/34490 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat +86 bp
0.003
SpliceAI acceptor gainat -115 bp
0.011
SpliceAI donor lossat +121 bp
0.000
SpliceAI donor gainat -23 bp
0.000
Pangolin splice lossmagnitude shown
-0.003
Pangolin splice gain
0.011
Other predictors
REVEL
0.262
BayesDel
-0.305
How the predictions were used
BP4SupportingMet (Supporting): REVEL 0.262 falls at or below the <=0.290 BP4_Supporting cutoff.
Details ▾Hide ▴
Reasoning
No governing VCEP/gene-specific cspec was found for RET in this case bundle, so generic ACMG in-silico calibration applies. REVEL score = 0.262 falls at/below the ClinGen SVI-recommended BP4_Supporting cutoff (REVEL <=0.290) per the published REVEL calibration (Pejaver et al., PMID 36413997), supporting a benign computational prediction at supporting strength (not moderate, since 0.262 is above the BP4_Moderate cutoff of <=0.183). SpliceAI max delta score = 0.011 is far below any splice-disruption threshold, consistent with no predicted splicing impact and not contradicting the benign missense in-silico signal. BayesDel score is available but excluded because no verified published threshold/PMID for BayesDel exists in this pipeline; the classification relies on REVEL alone as the calibrated missense predictor.
Rule
Generic ACMG/AMP (no gene-specific VCEP cspec available for RET in this case); REVEL calibrated thresholds per Pejaver et al. (PMID 36413997); BP4 applied at Supporting strength only (score does not reach the Moderate cutoff).
Evidence considered
REVEL score = 0.262 (source: local REVEL v1.3 predictor lookup), at/below the ClinGen SVI BP4_Supporting cutoff of <=0.290 for REVEL (Pejaver et al., PMID 36413997), consistent with a benign computational prediction at supporting strength.
SpliceAI predicts no significant splice impact (max delta score = 0.011; DS_AG=0.011, DS_AL=0.003, DS_DG=0.0, DS_DL=0.0), consistent with no splice-based pathogenic signal counteracting the benign in-silico missense prediction.
Still missing
BayesDel score (-0.304934) not used because no verified/citable calibration threshold is available for this pipeline.
PP3Not met: REVEL 0.262 is below the >=0.644 PP3_Supporting threshold.
Details ▾Hide ▴
Reasoning
No governing VCEP/gene-specific cspec was found for RET in this case bundle (cspec.found=false, generic_acmg framework_mode), so generic ACMG in-silico calibration applies. This is a missense substitution (NP_066124.1:p.(Ser829Asn)); the missense in-silico path governs. REVEL score = 0.262, well below the ClinGen SVI-recommended PP3_Supporting threshold (REVEL >=0.644), so REVEL does not support a pathogenic computational prediction. SpliceAI max delta score = 0.011, far below any splice-impact threshold (typically 0.2), so no splice-altering effect is predicted and the splice-impact path does not trigger PP3 either. BayesDel score (-0.304934) is available but this pipeline has no verified published threshold/PMID for BayesDel and per policy is treated as not_available/insufficiently calibrated, so it is not used to support or refute PP3. Overall, no calibrated computational tool supports a deleterious/splice-disrupting prediction for this variant.
Rule
Generic ACMG/AMP (no gene-specific VCEP cspec available for RET in this case); REVEL calibrated thresholds per Pejaver et al. (PMID 36413997); SpliceAI screened as secondary splice-impact check for this missense variant.
Evidence considered
REVEL score = 0.262 (source: local REVEL v1.3 predictor lookup), below the ClinGen SVI PP3_Supporting cutoff of >=0.644 established for REVEL calibration (Pejaver et al., PMID 36413997).
SpliceAI predicts no significant splice impact for this variant: DS_AG=0.011, DS_AL=0.003, DS_DG=0.0, DS_DL=0.0, max delta score=0.011 -- well under typical splice-impact thresholds, so no splice-disruption evidence supports PP3.
Still missing
No BayesDel-calibrated threshold with a citable publication is available to this pipeline; BayesDel score exists but cannot be used for PP3.
BP7N/ANot applicable: missense substitution, not a synonymous variant.
Details ▾Hide ▴
Reasoning
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_020975.5:c.2486G>A in RET is a missense substitution predicted to produce NP_066124.1:p.(Ser829Asn). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
Rule
deterministic_prefilter: requires_synonymous
Evidence considered
Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.262. BayesDel score = -0.304934.
6 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Richards S et al. · 2015 May
The ACMG/AMP consensus framework describes cis/trans testing as relevant to allelic criteria: a variant in trans with a pathogenic variant can support PM3 in a recessive disorder, while a second variant in cis can support BP2; it also describes trans with a pathogenic variant as BP2-supporting in a dominant disease model.
Testing parental samples to determine whether the variant occurs in cis (the same copy of the gene) or in trans (different copies of the gene) can be important for assessing pathogenicity. For example, when two heterozygous variants are identified in a gene for a recessive disorder, if one variant is known to be pathogenic, then determining that the other variant is in trans can be considered moderate evidence for pathogenicity of the latter variant (PM3). ... In contrast, finding the second variant in cis would be supporting evidence, though not definitive, for a benign role (BP2). In the context of dominant disorders, the detection of a variant in trans with a pathogenic variant can be considered supporting evidence for a benign impact (BP2).
Location Section PM3/BP2, Cis/trans testing
Context ACMG/AMP consensus recommendations for clinical sequence-variant interpretation; this publication was consulted for generic PM3/BP2 definitions and does not report the case variant.
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma.
Wells SA Jr et al. · 2015
This ATA guideline reviews phenotype associations for specific RET mutations in hereditary medullary thyroid carcinoma and discusses MEN2 disease manifestations. The searched full text did not identify NM_020975.5:c.2486G>A, p.Ser829Asn, or patient-level phenotype data for this exact variant.
Each of the 4 guidelines described the disease phenotypes associated with specific RET mutations in hereditary MTC and recommended timing of early thyroidectomy based on the specific RET mutation.
Page 8, section [B] Etiology of sporadic and hereditary MTC
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
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= 1.85996e-06; MAF= 0.00019%, 3/1612934 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66594e-05; MAF= 0.00167%, 1/60026 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.0213e-06; MAF= 0.00040%, 1/248676 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89939e-05; MAF= 0.00290%, 1/34490 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 1791991)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.262. BayesDel score = -0.304934.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RET, a receptor tyrosine kinase, is altered by mutation in medullary thyroid cancers and by chromosomal rearrangement in lung cancers, papillary thyro
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.
This variant was interpreted by pipeline 7.1.0.
The current version is 11.0.07.
Re-running queues a fresh interpretation; the result replaces this page when complete.
Re-runs are not free. Blank draws on today's public interpretation allowance; with a code, it uses one of that code's uses.