Classification rationale

PM2 BP4 VUS

RET c.2895G>T missense

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and Canada (AF 0), below the <0.1% threshold. BP4 (Supporting): SpliceAI max delta 0.00 and BayesDel −0.186 predict no impact on the gene product. VUS: PM2 + BP4 (one supporting each) satisfies no Pathogenic, Likely Pathogenic, Benign, or Likely Benign rule in the generic ACMG/AMP 2015 combination table.

PM2 + BP4 → VUS

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.

Gene diagram · NM_020975.5 · variants mapped to exon structure

RET NM_020975.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met (supporting): absent from gnomAD v2.1, v4.1, and Canada (AF 0), below the <0.1% threshold.

Absent from gnomAD v2.1 (exome)Absent from gnomAD v4.1 (exome)Absent from gnomAD-Canada v1.0 (HostSeq genomes); AC=0, AN=0, AF=0.0, hom=0

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP4 supporting Benign

Met (supporting): SpliceAI max delta 0.00 and BayesDel −0.186 both predict no impact (REVEL 0.529 indeterminate).

SpliceAI max delta = 0.00 (< 0.1): no predicted splice impact (BP4 splicing sub-path)BayesDel noAF score = -0.186199: predicted tolerated/benign (BP4 missense sub-path)REVEL v1.3 score = 0.529: intermediate, no call (not conflicting)

spliceai ↗

Assessed · not applied · 10 not met · 11 not assessed

Pathogenic

PS1 Not met: no established pathogenic variant produces the same p.Lys965Asn change; the only ClinVar entry is a 1-star VUS.

PS2 Not assessed: no de novo occurrence or parental testing for this variant is recorded in any source.

PS3 Not assessed: no functional studies exist; OncoKB reports no variant-specific evidence and COSMIC lacks the variant.

PS4 Not assessed: no case-control or case-series data exist for this variant in any retrieved source.

PM1 Not met: residue 965 shows no statistically significant cancer hotspot and no curated critical-domain annotation.

PM5 Not met: no pathogenic alternate missense at residue 965; the screen found zero same-residue candidates.

PM6 Not assessed: no de novo occurrence or parental genotypes are reported for this variant.

PP1 Not assessed: no co-segregation data — no affected relatives, pedigree, or segregation counts available.

PP2 Not assessed: missense is a known RET disease mechanism, but no gene-level benign-missense-rate data was available.

PP3 Not met: no in silico tool predicts damage — SpliceAI 0.00, BayesDel −0.186, REVEL 0.529 intermediate.

PP4 Not assessed: no proband phenotype or family history information was available for this variant.

PP5 Not met: no ClinVar expert-panel pathogenic assertion; the sole submission is a non-expert 1-star VUS.

Benign

BA1 Not met: absent from gnomAD (AF 0), far below the >1% general-population threshold.

BS1 Not met: allele frequency 0 does not exceed the expected frequency for this rare dominant disorder.

BS2 Not met: no observations in healthy controls — variant absent from gnomAD with no homozygous carriers.

BS3 Not assessed: no functional studies demonstrating a lack of damaging effect exist for this variant.

BS4 Not assessed: no family segregation data — no affected relatives tested or pedigree provided.

BP1 Not met: activating missense variants are an established RET disease mechanism, so missense cannot be assumed benign.

BP2 Not assessed: no in-trans or in-cis observation with a pathogenic variant is documented for this variant.

BP5 Not assessed: no reported case of this variant with an alternate molecular basis for disease.

BP6 Not met: no ClinVar expert-panel benign assertion; the sole submission is a non-expert 1-star VUS.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2454137)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.529. BayesDel score = -0.186199.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

25394175 ↗ 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. CLINVAR

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