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
RET
Final classification
VUS
PM2BP4
RET
c.2776C>T
p.His926Tyr
This variant
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-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
PM2 + BP4
→
VUS
Gene diagram
· NM_020975.6 · variants mapped to exon structure
RET
NM_020975.6
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 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
This variant is extremely rare in population databases: allele frequency 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), well below the 0.1% PM2 threshold. Absent from gnomAD-Canada.
gnomAD v2.1: AF=3.98e-6 (1/251480)0 homozygotes
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no deleterious impact. BayesDel score 0.114 is in the benign range (well below damaging threshold). SpliceAI delta score 0.02 predicts no splicing impact. REVEL score 0.571 is borderline but does not outweigh the other two lines of evidence.
BayesDel: 0.114 (benign rangeno damaging effect)SpliceAI: max delta 0.02 (no splice impact predicted)
Assessed · not applied
· 18 not met · 1 not assessed
Pathogenic
PS1
No known pathogenic missense variant has been established at the same amino acid residue (His926).
PS2
No de novo observation confirmed for this variant.
PS3
No well-established functional studies supporting a damaging effect have been identified.
PS4
No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls.
PM1
Residue His926 is located within the tyrosine kinase domain of RET but is not in a statistically significant mutational hotspot.
PM6
No assumed de novo observation without confirmation of paternity and maternity has been reported for this variant.
PP1
No co-segregation data are available for this variant.
PP2
Insufficient data to determine the rate of benign missense variation in RET specifically.
PP3
In silico predictions are conflicting and do not provide multiple lines of evidence supporting a deleterious effect.
PP4
No patient phenotype or family history data are available for assessment.
PP5
No reputable source has recently reported this variant as pathogenic.
Benign
BA1
The variant is extremely rare, not common.
BS1
The variant allele frequency (0.00040% in v2.1, 0.00012% in v4.1) is far below the 0.3% BS1 threshold for a dominant disorder.
BS2
No homozygotes have been observed in gnomAD v2.1 or v4.1, and no healthy adult homozygous or hemizygous observation has been reported.
BS3
No well-established functional studies demonstrating no damaging effect have been identified.
BS4
No segregation data are available to assess lack of co-segregation with disease.
BP2
No phase data are available.
BP5
No case has been reported where this variant is found in an individual with an alternate molecular basis for disease.
BP6
No reputable source has reported this variant as benign.
N/A · 7
PVS1 · PM3 · PM4 · PM5 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
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
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
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
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 578321)
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
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
COSMIC
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
Triaged references · 5 PMIDs not cited in assessment
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