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RET
Final classification
VUS
RET c.2895G>T · p.Lys965Asn
RET

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and Canada (AF 0), below the <0.1% threshold.

Gene
RET
Transcript
NM_020975.5
HGVS · transcript:coding
NM_020975.5:c.2895G>T
Consequence
N/A
GRCh38
chr10:43123764 G>T
GRCh37
chr10:43619212 G>T
Basis VUS: only PM2 (supporting) and BP4 (supporting) were met — one pathogenic-supporting plus one benign-supporting satisfies no combination rule.
VUS: only PM2 (supporting) and BP4 (supporting) were met — one pathogenic-supporting plus one benign-supporting satisfies no combination rule.
Classification rationale
PM2 BP4 VUS
RET c.2895G>T

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
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
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
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)
Assessed · not applied
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 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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.
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2454137)
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.529. BayesDel score = -0.186199.
Functional / OncoKB screenshot
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 screenshot
COSMIC
Cancer hotspots screenshot
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.
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