About RET
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RET c.2776C>T, p.(His926Tyr)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
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.
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.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
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.
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
2 / 1,613,376 alleles
gnomAD v4.1: 2 / 1,613,376 alleles. Recorded AF 1.23964e-06. Recorded homozygote count 0.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
3 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV60689597, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 19 not met · 1 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=3.98e-6 (1/251
- 480)
- 0 homozygotes
- gnomAD v4.1: AF=1.24e-6 (2/1
- 613
- 376)
- gnomAD-Canada: absent
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.114 (benign range
- no damaging effect)
- SpliceAI: max delta 0.02 (no splice impact predicted)
- REVEL: 0.571 (borderline
- not strongly pathogenic)
Sources
Not met · 19 · evaluated, threshold not reached
PS1 No known pathogenic missense variant has been established at the same amino acid residue (His926). PM5 candidate search found zero same-residue pathogenic comparators. Details ▾Hide ▴
Evidence considered
- Zero same-residue pathogenic comparator variants identified
- No ClinVar expert panel P/LP submissions at His926
Sources
pm5_candidates
PS2 No de novo observation confirmed for this variant. No publication or ClinVar submission reports a de novo event with confirmed maternity and paternity. Details ▾Hide ▴
PS3 No well-established functional studies supporting a damaging effect have been identified. OncoKB reports unknown oncogenic effect without variant-specific functional evidence. No publication describes functional characterization of p.His926Tyr. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence
- No functional study identified in literature for this variant
Still missing
- No functional characterization of p.His926Tyr available
Sources
PS4 No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls. Three clinical laboratories report this variant as VUS in ClinVar, but no prevalence comparison data are available. Details ▾Hide ▴
Evidence considered
- 3 ClinVar submissions
- all VUS
- No case-control or cohort enrichment data
Still missing
- No affected vs. control prevalence data
Sources
PM1 Residue His926 is located within the tyrosine kinase domain of RET but is not in a statistically significant mutational hotspot. Hotspot analysis did not identify this residue as significantly enriched for pathogenic variation. Details ▾Hide ▴
Evidence considered
- Hotspots analysis: not in a statistically significant hotspot
- Residue not marked as significant in any hotspot database
PM6 No assumed de novo observation without confirmation of paternity and maternity has been reported for this variant. Details ▾Hide ▴
PP1 No co-segregation data are available for this variant. No family studies have been reported. Details ▾Hide ▴
Evidence considered
- No co-segregation or family study data identified
Still missing
- No segregation data available
PP3 In silico predictions are conflicting and do not provide multiple lines of evidence supporting a deleterious effect. REVEL score 0.571 is borderline (just above 0.5 threshold), but BayesDel score 0.114 is clearly in the benign range, and SpliceAI delta score 0.02 predicts no splicing impact. These do not constitute multiple concordant lines of computational evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.571 (borderline pathogenic)
- BayesDel: 0.114 (benign range)
- SpliceAI: max delta 0.02 (no splice impact)
Sources
PP4 No patient phenotype or family history data are available for assessment. The ClinVar submissions do not include detailed clinical phenotype information. Details ▾Hide ▴
Evidence considered
- ClinVar condition labels: Not Provided or empty
Still missing
- No patient phenotype data available
Sources
PP5 No reputable source has recently reported this variant as pathogenic. ClinVar classification is Uncertain Significance from three clinical laboratories. All reviewed publications are clinical guidelines or practice recommendations that do not mention this specific variant. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS (3 clinical labs)
- No publication reports this variant as pathogenic
Sources
BA1 The variant is extremely rare, not common. Allele frequency is 0.00040% in gnomAD v2.1 and 0.00012% in gnomAD v4.1, far below the 1% BA1 threshold. Details ▾Hide ▴
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. This variant is not too common for a disease-causing variant. Details ▾Hide ▴
Evidence considered
- Allele frequency well below 0.3% in all populations
Sources
BS2 No homozygotes have been observed in gnomAD v2.1 or v4.1, and no healthy adult homozygous or hemizygous observation has been reported. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 homozygotes
- gnomAD v4.1: 0 homozygotes
Sources
BS3 No well-established functional studies demonstrating no damaging effect have been identified. No publication provides functional characterization of p.His926Tyr. Details ▾Hide ▴
Evidence considered
- No functional studies of any kind identified for this variant
Still missing
- No functional characterization data available
Sources
BS4 No segregation data are available to assess lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
- No family or segregation studies identified
Still missing
- No segregation data available
BP2 No phase data are available. The variant has not been observed in trans with a known pathogenic RET variant or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Evidence considered
- No phase information available
Still missing
- No phase data available
BP5 No case has been reported where this variant is found in an individual with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available
Still missing
- No case data with alternate molecular diagnosis
BP6 No reputable source has reported this variant as benign. ClinVar classification is VUS, not benign or likely benign. Details ▾Hide ▴
PS5 No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain Significance from three clinical laboratories. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance (3 clinical labs
- single submitter review status)
Sources
Not assessed · 1 · no assessment recorded
PP2 Insufficient data to determine the rate of benign missense variation in RET specifically. RET has dual disease mechanisms: gain-of-function missense (MEN2) and loss-of-function (Hirschsprung disease). Missense constraint metrics (e.g., Z-score) are not explicitly available in the evidence brief. Details ▾Hide ▴
Evidence considered
- RET has both GOF (MEN2
- MTC) and LOF (Hirschsprung disease) disease mechanisms
Still missing
- RET missense constraint metrics not explicitly available
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.His926Tyr), not a null variant (nonsense, frameshift, or canonical splice site). The variant does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution
- Not a nonsense
- frameshift
- or canonical ±1
- 2 splice site variant
- PVS1 variant assessment confirms bucket='other'
- apply_generic_pvs1_framework=false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant; no phase data or recessive disease context applicable here. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo established pathogenic missense variant at the same residue (His926) was identified. PM5 candidate search returned zero same-residue pathogenic comparators. Details ▾Hide ▴
Evidence considered
- Zero same-residue pathogenic comparator variants identified
Sources
pm5_candidates
BP1 N/ARET disease mechanisms include both loss-of-function (Hirschsprung disease via truncating variants) and gain-of-function (MEN2/MTC via activating missense). The gene does not primarily cause disease through truncating variants. BP1 (missense in gene where truncating variants primarily cause disease) does not apply. Details ▾Hide ▴
Evidence considered
- RET has dual disease mechanisms: GOF missense (MEN2) and LOF (Hirschsprung disease)
- Missense is a recognized disease mechanism for RET-related disorders
Sources
pvs1_gene_context
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (c.2776C>T, p.His926Tyr), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution
- not synonymous
Identifiers
- Gene
- RET
- Transcript
- NM_020975.6
- Coding (HGVS c.)
- NM_020975.6:c.2776C>T
- Protein (HGVS p.)
- NP_066124.1:p.(His926Tyr)
- GRCh38
- chr10:43121991 C>T
- GRCh37
- chr10:43617439 C>T
- ClinVar
- 1801002, 578321
- COSMIC
- COSV60689597
Gene diagram
Every interpreted variant in RET, mapped onto the exon structure of NM_020975.6. Select a row to find it on the plot.
RETNM_020975.6
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.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
2 / 1,613,376 alleles
AF 1.24e-06 · 0 homozygotes
gnomAD v2.1
1 / 251,480 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,613,376 alleles · 0 hom
| Admixed American1 / 59,986 | 1.7e-05 |
| European (non-Finnish)1 / 1,179,608 | 8.5e-07 |
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 / 251,480 alleles · 0 hom
| Admixed American1 / 34,592 | 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= 1.23964e-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).
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.571
- BayesDel
- 0.114
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.114 (benign range
- no damaging effect)
- SpliceAI: max delta 0.02 (no splice impact predicted)
- REVEL: 0.571 (borderline
- not strongly pathogenic)
Sources
PP3 In silico predictions are conflicting and do not provide multiple lines of evidence supporting a deleterious effect. REVEL score 0.571 is borderline (just above 0.5 threshold), but BayesDel score 0.114 is clearly in the benign range, and SpliceAI delta score 0.02 predicts no splicing impact. These do not constitute multiple concordant lines of computational evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.571 (borderline pathogenic)
- BayesDel: 0.114 (benign range)
- SpliceAI: max delta 0.02 (no splice impact)
Sources
BP7 N/AThis is a missense variant (c.2776C>T, p.His926Tyr), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.571. BayesDel score = 0.113536.
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 11739416 ↗Guidelines for diagnosis and therapy of MEN type 1 and type 2.Brandi ML et al. · 2001Consensus guidelines for diagnosis and therapy of MEN type 1 and type 2. Discusses RET gene mutations in the context of MEN2 syndromes at the gene level. NM_020975.6:c.2776C>T (p.His926Tyr) was not identified in this paper.Does not name this variant
-
PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004NSGC practice recommendations for cancer genetic risk assessment and counseling. Mentions RET in a table of hereditary cancer syndromes (MEN2) at the gene level only. NM_020975.6:c.2776C>T (p.His926Tyr) was not identified in this paper.Does not name this variant
-
PMID 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.Hampel H et al. · 2015ACMG/NSGC practice guideline for cancer predisposition assessment referral indications. RET is referenced under MEN2 and medullary thyroid cancer criteria at the gene level only. NM_020975.6:c.2776C>T (p.His926Tyr) was not identified in this paper.Does not name this variant
-
PMID 25810047 ↗Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma.Wells SA Jr et al. · 2015Revised American Thyroid Association guidelines for management of medullary thyroid carcinoma. Provides detailed discussion of RET codon-level genotype-phenotype correlations for known MEN2 mutations but does not mention NM_020975.6:c.2776C>T (p.His926Tyr).Does not name this variant
-
PMID 26389271 ↗Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on endocrine and neuroendocrine neoplasias. Provides gene-level overview of RET in MEN2 syndromes. NM_020975.6:c.2776C>T (p.His926Tyr) was not identified in the available abstract.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,613,376 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
3 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/578321/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-43617439-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-43121991-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-43121991-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_020975.6%3Ac.2776…
- OncoKB ↗www.oncokb.org/gene/RET/H926Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=136286908
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
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= 1.23964e-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).
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
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 previously been reported in somatic cancers (COSMIC; COSV60689597, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.