Analysis in progress
Initialising…
0%
complete
This report is still being assembled — sections appear as each stage finishes. It isn't final yet.
RET
Final classification
VUS
RET c.2776C>T · p.His926Tyr
RET

This variant is extremely rare in population databases, observed at an allele frequency of 0.00040% in gnomAD v2.1 (1/251,480 alleles, no homozygotes) and 0.00012% in gnomAD v4.1 (2/1,613,376 alleles, no homozygotes), meeting PM2 at supporting strength.

Gene
RET
Transcript
NM_020975.6
HGVS · transcript:coding
NM_020975.6:c.2776C>T
Consequence
N/A
GRCh38
chr10:43121991 C>T
GRCh37
chr10:43617439 C>T
Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2 BP4 VUS
RET c.2776C>T

This variant is extremely rare in population databases, observed at an allele frequency of 0.00040% in gnomAD v2.1 (1/251,480 alleles, no homozygotes) and 0.00012% in gnomAD v4.1 (2/1,613,376 alleles, no homozygotes), meeting PM2 at supporting strength.1 Multiple in silico tools predict no deleterious effect: BayesDel score 0.114 falls in the benign range, and SpliceAI delta score 0.02 predicts no splicing impact, meeting BP4 at supporting benign strength. REVEL score 0.571 is borderline and does not outweigh the other two lines of evidence.2 This variant has been reported in ClinVar as Uncertain Significance by three clinical laboratories (ClinVar Variation ID: 578321). Three clinical laboratories independently classified it as VUS (SCV004028319, SCV002747231, SCV000830083). No expert panel review is available.3 This variant has been observed in somatic cancers (COSMIC: COSV60689597, n=2) but lacks germline disease association evidence. Overall classification: Uncertain Significance — one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) yield insufficient evidence to classify this variant as either pathogenic or benign. This is consistent with the ClinVar VUS classification.4

PM2 + BP4 VUS
2 bayesdelspliceai ↗revel
4 generic_acmg_combination_rules
Gene diagram · NM_020975.6 · variants mapped to exon structure
RET NM_020975.6
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      Research & evidence
      Population frequency
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This variant is present in gnomAD v4.1 (AF= 1.23964e-06; MAF= 0.00012%, 2/1613376 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66706e-05; MAF= 0.00167%, 1/59986 alleles, homozygotes = 0).
      v2.1
      This variant is present in gnomAD v2.1 (AF= 3.97646e-06; MAF= 0.00040%, 1/251480 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
      🇨🇦 CA
      Absent from gnomAD-Canada v1.0.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.00012% · 2 / 1,613,376
      0 hom
      Admixed American
      1 / 59,986
      0.0017%
      European (non-Finnish)
      1 / 1,179,608
      8.5e-05%
      + 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
      gnomAD v2.1
      0.0004% · 1 / 251,480
      0 hom
      Admixed American
      1 / 34,592
      0.0029%
      + 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
      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 (3 clinical laboratories). (ClinVarID = 578321)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.571. BayesDel score = 0.113536.
      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 previously been reported in somatic cancers (COSMIC; COSV60689597, n = 2 times).
      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 · 5 PMIDs not cited in assessment
      11739416 ↗ Guidelines for diagnosis and therapy of MEN type 1 and type 2. CLINVAR
      15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR
      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
      25810047 ↗ Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. CLINVAR
      26389271 ↗ Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®): Health Professional Version. CLINVAR