About RET
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RET c.2711C>T, p.(Ser904Phe)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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: 6
Benign evidence criteria: 0
Pathogenic criteria applied · 6
PS3Supporting
PS3 · supporting
In vitro functional studies demonstrate that the S904F substitution increases RET kinase ATP affinity, accelerates autophosphorylation, and confers gain-of-function transforming activity. These functional defects are consistent with the established gain-of-function mechanism of RET in MEN2 and medullary thyroid carcinoma.
PM1Moderate
PM1 · moderate
The variant is located in the activation loop of the RET tyrosine kinase domain (codon 904, situated between autophosphorylation residues Y900 and Y905), a critical and well-established functional domain. The RET kinase domain is a known mutational hotspot for pathogenic MEN2-associated variants, and no benign variation has been established at this residue within the activation loop.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD-Canada and is present in gnomAD v4.1 at an extremely low allele frequency (1/1,613,158 alleles, AF = 6.2e-7), well below the PM2 threshold of 0.1%. No homozygotes have been observed.
PP1Moderate
PP1 · moderate
The variant cosegregates with medullary thyroid carcinoma in multiple affected family members across at least two families. In the largest reported family (PMID:33167350), 7 of 10 carriers developed MTC across multiple generations (average age at diagnosis 46.3 years). A prior report describes a father and son both affected with adult-onset MTC. RET is a gene definitively known to cause MEN2/FMTC.
PP3Supporting
PP3 · supporting
REVEL score of 0.821 exceeds the 0.7 threshold for pathogenic prediction, supporting a deleterious effect on protein function. BayesDel score of 0.3192 provides borderline additional support. SpliceAI predicts no splicing impact (max delta = 0.0). Multiple in silico algorithms support a deleterious prediction.
PP4Supporting
PP4 · supporting
The variant has been observed in multiple individuals with medullary thyroid carcinoma, a phenotype that is highly specific for RET-related hereditary cancer syndromes (MEN2A, MEN2B, FMTC). MTC is a hallmark feature of RET-associated disease with high positive predictive value.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 supporting, PM1 moderate, PM2 supporting, PP1 moderate, PP3 supporting, PP4 supporting; combination = 2 moderate + 4 supporting, which maps to Likely Pathogenic.
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
1 / 1,613,158 alleles
gnomAD v4.1: 1 / 1,613,158 alleles. Recorded AF 6.19902e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
2 Likely pathogenic · 1 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV60693575, 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.
26 criteria with recorded statuses: 6 met · 16 not met · 1 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_020975.6:c.2711C>T (p.Ser904Phe) is a missense variant in exon 15 of the RET gene, located in the activation loop of the tyrosine kinase domain.
This variant is absent from gnomAD v2.1 and gnomAD-Canada, and is present in gnomAD v4.1 at an extremely low allele frequency of 6.2e-7 (1/1,613,158 alleles), meeting PM2_supporting.
The variant is located in the activation loop of the RET kinase domain (codon 904, between autophosphorylation residues Y900 and Y905), a critical functional domain and known mutational hotspot for MEN2-associated variants, meeting PM1_moderate.
In vitro functional studies demonstrate that S904F increases RET kinase ATP affinity, accelerates autophosphorylation, and confers gain-of-function transforming activity, consistent with the established pathogenic mechanism of RET in MEN2, meeting PS3_supporting.
The variant cosegregates with medullary thyroid carcinoma in multiple affected family members across at least two families; in the largest reported family, 7 of 10 carriers developed MTC across multiple generations, meeting PP1_moderate.
REVEL in silico prediction score of 0.821 supports a deleterious effect on protein function, meeting PP3_supporting.
The variant has been observed in multiple individuals with medullary thyroid carcinoma, a phenotype highly specific for RET-related hereditary cancer syndromes, meeting PP4_supporting.
Two moderate criteria (PM1, PP1) and four supporting criteria (PS3, PM2, PP3, PP4) are met. Per ACMG/AMP 2015 combination rules (PMID:25741868), this combination is consistent with a classification of Likely Pathogenic.
No criteria match.
Met · 6
PS3 SupportingIn vitro functional studies demonstrate that the S904F substitution increases RET kinase ATP affinity, accelerates autophosphorylation, and confers gain-of-function transforming activity. These functional defects are consistent with the established gain-of-function mechanism of RET in MEN2 and medullary thyroid carcinoma. Details ▾Hide ▴
Evidence considered
- PMID:29434222: S904F mutant CCDC6-RET showed increased ATP affinity (Km[ATP])
- accelerated autophosphorylation kinetics
- and higher catalytic efficiency vs wild-type in in vitro kinase assays using purified RET kinase domains
- Ba/F3 cells expressing S904F showed IL3-independent growth
- the mutation is noted as 'a germline oncogenic mutation responsible for the development of familial thyroid cancer.'
- PMID:21810974 (Cosci et al. 2011): in silico and in vitro analysis of S904F among six rare RET mutations
- S904F showed the highest in silico score (65) and demonstrated transforming activity in NIH3T3 fibroblast assays
- consistent with low-aggressiveness MEN2-associated variant.
Still missing
- Functional studies are from somatic/vitro contexts rather than dedicated germline-validated functional assays
- strength assigned as supporting to reflect this.
Sources
PM1 ModerateThe variant is located in the activation loop of the RET tyrosine kinase domain (codon 904, situated between autophosphorylation residues Y900 and Y905), a critical and well-established functional domain. The RET kinase domain is a known mutational hotspot for pathogenic MEN2-associated variants, and no benign variation has been established at this residue within the activation loop. Details ▾Hide ▴
Evidence considered
- PMID:29434222: 'The serine 904 residue is located in between two autophosphorylation tyrosines Y900 and Y905 within the canonical activation loop (AL) of RET kinase.'
- The RET kinase domain activation loop is a well-established critical functional domain
- known pathogenic MEN2 variants cluster in the kinase domain.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD-Canada and is present in gnomAD v4.1 at an extremely low allele frequency (1/1,613,158 alleles, AF = 6.2e-7), well below the PM2 threshold of 0.1%. No homozygotes have been observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (0 alleles).
- gnomAD v4.1: 1/1
- 613
- 158 alleles
- AF = 6.2e-7
- highest subpopulation AF = 1.6e-5 (Remaining individuals
- 1/62
- 414).
- gnomAD-Canada v1.0: absent.
Sources
PP1 ModerateThe variant cosegregates with medullary thyroid carcinoma in multiple affected family members across at least two families. In the largest reported family (PMID:33167350), 7 of 10 carriers developed MTC across multiple generations (average age at diagnosis 46.3 years). A prior report describes a father and son both affected with adult-onset MTC. RET is a gene definitively known to cause MEN2/FMTC. Details ▾Hide ▴
Evidence considered
- PMID:33167350: family 91-O-03: 8 tested carriers + 2 obligate carriers across multiple generations
- 7/10 developed MTC at average age 46.3 years. Highly penetrant but late-onset
- slowly progressing MTC. Prior published family with father and son affected by adult-onset MTC cited as reference [25].
Sources
PP3 SupportingREVEL score of 0.821 exceeds the 0.7 threshold for pathogenic prediction, supporting a deleterious effect on protein function. BayesDel score of 0.3192 provides borderline additional support. SpliceAI predicts no splicing impact (max delta = 0.0). Multiple in silico algorithms support a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.821 (>0.7 pathogenic threshold).
- BayesDel: 0.3192 (borderline
- below typical strong pathogenic threshold).
- SpliceAI: max delta = 0.0 (no predicted splicing impact).
- ClinVar submission SCV005930562 (Ambry Genetics): cites PP3 based on in silico analysis.
Sources
PP4 SupportingThe variant has been observed in multiple individuals with medullary thyroid carcinoma, a phenotype that is highly specific for RET-related hereditary cancer syndromes (MEN2A, MEN2B, FMTC). MTC is a hallmark feature of RET-associated disease with high positive predictive value. Details ▾Hide ▴
Evidence considered
- PMID:33167350: 7 carriers with MTC in one family
- additional family with MTC reported. MTC is the sentinel feature of RET-related MEN2/FMTC.
- ClinVar VariationID 24963: classified as LP by 2 clinical laboratories in the context of MEN2/FMTC.
Sources
Not met · 16 · evaluated, threshold not reached
PS1 No evidence is available that a different nucleotide change at codon 904 producing the same amino acid substitution (p.Ser904Phe) has been established as pathogenic; PS1 cannot be applied without a known pathogenic comparator arising from an alternative nucleotide change at the same residue. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change at NM_020975.6:c.2711 resulting in p.Ser904Phe was identified in ClinVar or the literature as a known pathogenic variant.
Still missing
- No same-amino-acid different-nucleotide comparator established as pathogenic.
PS2 No de novo observation with confirmed paternity and maternity has been reported for this variant; the variant has been observed as inherited in multiple family members (PMID:33167350). Details ▾Hide ▴
Evidence considered
- PMID:33167350: variant segregates as inherited in a multi-generation family with MTC
- not de novo.
Still missing
- No de novo report available.
Sources
PS4 The variant has been observed in affected families but there are insufficient case-control data to demonstrate a statistically significant increased prevalence in affected individuals compared to population controls. Only two families with MTC are reported, and the variant is not observed at sufficient scale in case-control cohorts. Details ▾Hide ▴
Evidence considered
- PMID:33167350: 7/10 carriers affected with MTC in one family
- one additional family with father-son pair referenced as prior report. Insufficient for statistical case-control comparison.
Still missing
- No case-control study with statistical power for this rare variant.
Sources
PM5 No same-residue comparator missense variants with an established pathogenic classification were identified in ClinVar or the literature; classic PM5 semantics (different amino acid change at the same residue already established as pathogenic) cannot be applied. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json: found=false
- no same-residue pathogenic comparators identified
- recommendation is not_applicable.
Still missing
- No pathogenic comparators at codon 904 with a different amino acid change identified.
Sources
pm5_candidates
PM6 No de novo observation (even without confirmed paternity/maternity) has been reported for this variant; the variant segregates as inherited in multiple families with MTC. Details ▾Hide ▴
Evidence considered
- PMID:33167350: variant is inherited
- not de novo
- observed across multiple generations in at least two families.
Still missing
- No de novo observation reported.
Sources
PP5 ClinVar classification is split between Likely pathogenic (2 labs) and Uncertain significance (1 lab) with review status of 'criteria provided, single submitter.' No expert panel or multi-submitter consensus exists. The available evidence has been independently evaluated; PP5 should not be applied when the underlying evidence is available for direct assessment. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 24963: 2 LP (ARUP
- Bologna)
- 1 VUS (Ambry)
- review status 'criteria provided
- single submitter'
- no expert panel classification.
Still missing
- No expert panel consensus classification.
Sources
BA1 The maximum population allele frequency in gnomAD (1.6e-5 in Remaining individuals) is far below the BA1 threshold of 1%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: max subpopulation AF = 1.6e-5 (0.0016%)
- well below BA1 threshold of 1%.
Sources
BS1 The maximum population allele frequency in gnomAD (1.6e-5) is far below the BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: max subpopulation AF = 1.6e-5 (0.0016%)
- well below BS1 threshold of 0.3%.
Sources
BS2 Only 1 allele observed in gnomAD v4.1 across 1.6 million alleles; insufficient observation in healthy adults to apply BS2, which requires observation in healthy adults for a disorder expected to have full penetrance at an early age. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1/1
- 613
- 158 alleles
- single heterozygous carrier
- no homozygotes. Insufficient healthy adult observations.
Sources
BS3 Available functional studies demonstrate gain-of-function effects (increased ATP affinity, accelerated autophosphorylation, transforming activity) consistent with a pathogenic mechanism, not a benign effect. BS3 is not supported. Details ▾Hide ▴
Evidence considered
- PMID:29434222: S904F shows increased ATP affinity
- accelerated autophosphorylation
- and transforming activity — gain-of-function
- not benign.
- PMID:21810974: S904F shows transforming activity in NIH3T3 assays — consistent with pathogenic gain-of-function.
Sources
BS4 The variant does segregate with disease in reported families. In PMID:33167350, 7 of 10 carriers across multiple generations developed MTC, and a prior report describes a father-son pair both affected. This is inconsistent with BS4 (lack of segregation). Details ▾Hide ▴
Evidence considered
- PMID:33167350: variant cosegregates with MTC in multiple family members across generations
- no evidence of non-segregation.
Sources
BP2 No evidence was identified that this variant has been observed in trans with a known pathogenic RET variant in a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No reports of S904F observed in trans with a pathogenic RET variant.
Still missing
- No trans configuration data available.
BP4 REVEL score of 0.821 supports a deleterious effect, contradicting BP4 which requires multiple lines of computational evidence suggesting no impact on gene product. BayesDel score of 0.3192 is borderline and does not overcome the strong REVEL prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.821 (>0.7
- pathogenic). BayesDel: 0.3192 (borderline). SpliceAI: 0.0 (no impact). Computational evidence trends toward deleterious
- not benign.
Sources
BP5 No evidence was identified that this variant has been found in a case with an alternate molecular basis for disease that would explain the phenotype independently. Details ▾Hide ▴
Evidence considered
- No reports of S904F occurring in individuals with an alternative molecular diagnosis explaining their MTC phenotype.
Still missing
- No alternate-molecular-basis data available.
BP6 No reputable source reports this variant as benign or likely benign. ClinVar classifications are Likely pathogenic (2 labs) or Uncertain significance (1 lab). Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 24963: classifications are LP (2) and VUS (1)
- no benign or likely benign classifications.
Sources
PS5 ClinVar classification for this variant is split: Likely pathogenic (2 clinical laboratories) and Uncertain significance (1 clinical laboratory), with review status of 'criteria provided, single submitter' and no expert panel consensus. The available evidence has been independently reviewed; PS5/PP5 should not be applied when the underlying evidence is available for evaluation. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 24963: 2 LP
- 1 VUS
- review status 'criteria provided
- single submitter'
- no expert panel classification.
Still missing
- No expert panel or multi-submitter consensus classification.
Sources
Not assessed · 1 · no assessment recorded
PP2 Insufficient gene-level missense constraint data (e.g., gnomAD Z-score, missense depletion metrics) were available to determine whether RET has a low rate of benign missense variation. HCI prior data was not available for this gene. Details ▾Hide ▴
Evidence considered
- HCI prior: gene_not_supported
- no gnomAD missense constraint metrics available in evidence_brief.
Still missing
- RET missense constraint Z-score and benign missense rate data not available.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis missense variant (c.2711C>T, p.Ser904Phe) does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants; PVS1 is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- PVS1 variant assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false
- missense substitutions are excluded from default PVS1 null-variant framework per PMC6185798.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. RET-associated MEN2 is caused by gain-of-function missense variants; truncating variants are not the primary disease mechanism. BP1 is therefore not applicable. Details ▾Hide ▴
Evidence considered
- RET MEN2 disease mechanism is gain-of-function via activating missense variants
- truncating (loss-of-function) variants do not represent the primary disease mechanism.
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This variant is a missense substitution (c.2711C>T, p.Ser904Phe) and is therefore not eligible for BP7. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Ser904Phe)
- not synonymous
- BP7 is restricted to silent/synonymous variants.
Identifiers
- Gene
- RET
- Transcript
- NM_020975.6
- Coding (HGVS c.)
- NM_020975.6:c.2711C>T
- Protein (HGVS p.)
- NP_066124.1:p.(Ser904Phe)
- GRCh38
- chr10:43120184 C>T
- GRCh37
- chr10:43615632 C>T
- ClinVar
- 963212, 24963, 665731
- COSMIC
- COSV60693575
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
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in RET
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,613,158 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,158 alleles · 0 hom
| Remaining individuals1 / 62,414 | 1.6e-05 |
0 alternate alleles recorded in 9 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19902e-07; MAF= 0.00006%, 1/1613158 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6022e-05; MAF= 0.00160%, 1/62414 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.821
- BayesDel
- 0.319
How the predictions were used
PP3 SupportingREVEL score of 0.821 exceeds the 0.7 threshold for pathogenic prediction, supporting a deleterious effect on protein function. BayesDel score of 0.3192 provides borderline additional support. SpliceAI predicts no splicing impact (max delta = 0.0). Multiple in silico algorithms support a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.821 (>0.7 pathogenic threshold).
- BayesDel: 0.3192 (borderline
- below typical strong pathogenic threshold).
- SpliceAI: max delta = 0.0 (no predicted splicing impact).
- ClinVar submission SCV005930562 (Ambry Genetics): cites PP3 based on in silico analysis.
Sources
BP4 REVEL score of 0.821 supports a deleterious effect, contradicting BP4 which requires multiple lines of computational evidence suggesting no impact on gene product. BayesDel score of 0.3192 is borderline and does not overcome the strong REVEL prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.821 (>0.7
- pathogenic). BayesDel: 0.3192 (borderline). SpliceAI: 0.0 (no impact). Computational evidence trends toward deleterious
- not benign.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This variant is a missense substitution (c.2711C>T, p.Ser904Phe) and is therefore not eligible for BP7. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Ser904Phe)
- not synonymous
- BP7 is restricted to silent/synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.821. BayesDel score = 0.3192.
8 paper records listed. 3 cited in the classification.
Cited in the classification
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PMID 21810974 ↗In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer.S904F was one of six rare germline RET mutations analyzed by in silico and in vitro assays for transforming activity. S904F received the highest in silico score (65) among the six variants tested and demonstrated transforming activity in NIH3T3 fibroblast focus formation assays, consistent with a gain-of-function pathogenic mechanism. The authors suggested assigning S904F to the lowest ATA risk level based on relatively high transforming activity but low clinical aggressiveness.→ PS3 Names this variant
Source detail
Germline and somatic RET oncogene mutations are found in 98% hereditary and 40% sporadic medullary thyroid carcinomas. Our aim was to analyse by in silico and in vitro assays the transforming activity of six rare RET mutations (T338I, V648I, M918V, A883T, S904F and M848T). [...] The in silico analysis showed the highest score value (i.e. 65) for S904F
Location Abstract; cited by PMID:33167350 as reference [26] (Cosci et al. 2011)
Context In silico prediction tools; NIH3T3 fibroblast focus formation assay for transforming activity
-
PMID 29434222 ↗A secondary RET mutation in the activation loop conferring resistance to vandetanib.Nakaoku T et al. · 2018 Feb 12S904F secondary mutation identified in the RET kinase domain activation loop of a CCDC6-RET fusion-positive lung adenocarcinoma that developed resistance to vandetanib. In vitro kinase assays demonstrated that S904F increases ATP affinity, accelerates autophosphorylation, and enhances catalytic efficiency compared to wild-type RET. Ba/F3 cells expressing S904F showed IL3-independent growth. The authors note that the same mutation is a known germline oncogenic mutation responsible for familial medullary thyroid carcinoma.→ PS3 Names this variant
Source detail
Discovery of a S904F secondary mutation in the RET kinase domain [...] Targeted deep sequencing of cancer-related genes from genomic DNA identified a serine-to-phenylalanine substitution at codon 904 (S904F) in RET as the only non-synonymous mutation in the resistant tumor
Location Abstract; Results (Discovery of a S904F secondary mutation); Results (Vandetanib resistance is related to increased ATP affinity); Figure 1d; Figure 2a-c; Figure 3a-d; Discussion para 2
Context In vitro kinase assay using purified recombinant RET kinase domain (aa 658-1072) expressed in Sf9 insect cells; H1299 lung cancer cells transiently expressing CCDC6-RET; Ba/F3 cells with lentiviral CCDC6-RET transduction; X-ray crystallography of S904F RET kinase domain at 2.3A; thermal shift assay; molecular dynamics simulation
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PMID 33167350 ↗Results and Clinical Interpretation of Germline RET Analysis in a Series of Patients with Medullary Thyroid Carcinoma: The Challenge of the Variants of Uncertain Significance.Innella G et al. · 2020 Nov 5p.Ser904Phe identified as a variant of uncertain significance in a family (91-O-03) with multiple members affected by medullary thyroid carcinoma. Eight individuals were tested and found to carry the variant, with two additional obligate carriers. Seven of ten carriers developed slowly progressing MTC at an average age of 46.3 years; none manifested pheochromocytoma or hyperparathyroidism. The authors conclude that the variant is highly penetrant but causes late-onset, low-aggressiveness MTC, suggesting that screening recommended for carriers of lowest-risk ATA mutations is appropriate.→ PP1 → PP4 Names this variant
Source detail
The p.Ser904Phe variant was found in a family with several members affected by MTC (Figure 1): eight individuals were tested and found to carry the variant, while two other relatives were obligate carriers. Out of 10 carriers, seven developed slowly progressing MTC at an average age of 46.3 years and none manifested other RET-related problems.
Location Section 2.3 (Families with Unclassified Variants), para 1; Table 3; Figure 1; Discussion para 5; Section 4.4
Context Clinical cohort study of 163 subjects undergoing RET genetic testing at a cancer genetics clinic; segregation analysis and genotype-phenotype correlation.
Other recorded publications
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PMID 21863057 ↗Clinical utility gene card for: multiple endocrine neoplasia type 2.Raue F et al. · 2012Clinical utility gene card for multiple endocrine neoplasia type 2, providing an overview of disease characteristics, testing methods, and clinical utility of RET genetic testing. NM_020975.6:c.2711C>T (p.Ser904Phe) was not identified in this paper.Does not name this variant
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PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG policy statement regarding updated recommendations for analysis and reporting of secondary findings in clinical genome-scale sequencing. NM_020975.6:c.2711C>T (p.Ser904Phe) was not identified in this paper.Does not name this variant
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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 on referral indications for cancer predisposition assessment, including referral criteria for MEN2 based on medullary thyroid cancer diagnosis. NM_020975.6:c.2711C>T (p.Ser904Phe) was not identified in this paper.Does not name this variant
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PMID 26389271 ↗Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®): Health ProfessionalPDQ cancer genetics summary on endocrine and neuroendocrine neoplasias. NM_020975.6:c.2711C>T (p.Ser904Phe) was not identified in this paper.Does not name this variant
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PMID 27854360 ↗Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.ACMG SF v2.0 recommendations for reporting secondary findings in clinical exome and genome sequencing, listing RET as a medically actionable gene for MEN2/FMTC. NM_020975.6:c.2711C>T (p.Ser904Phe) was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,613,158 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Likely pathogenic · 1 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/24963/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-43615632-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-43120184-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-43120184-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_020975.6%3Ac.2711…
- OncoKB ↗www.oncokb.org/gene/RET/S904F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=136265834
- 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= 6.19902e-07; MAF= 0.00006%, 1/1613158 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6022e-05; MAF= 0.00160%, 1/62414 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 24963)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.821. BayesDel score = 0.3192.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV60693575, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.