NM_020975.6:c.2410G>T (p.Val804Leu) is a missense variant in exon 14 of the RET gene, located in the tyrosine kinase domain. This variant is extremely rare in population databases, with allele frequencies of 0.00043% in gnomAD v2.1 (1/232,600 alleles), 0.00131% in gnomAD v4.1 (21/1,605,504 alleles; grpmax FAF=0.000804%), and absent from gnomAD-Canada.1 The variant has been reported as Pathogenic in ClinVar by 18 clinical laboratories with 19 total submissions and no conflicting interpretations.2 Well-established functional studies demonstrate that p.Val804Leu is a gain-of-function mutation causing constitutive RET kinase activation, consistent with the known oncogenic mechanism in MEN2 and FMTC.3 The variant has been reported in multiple families with MEN2A/FMTC, with co-segregation of the variant with disease phenotype observed in extended kindreds. Codon 804 lies within the RET tyrosine kinase domain, a well-established mutational hotspot in MEN2 and FMTC without benign missense variation. Under the generic ACMG/AMP 2015 framework (PMID:25741868), the combination of PS3 (strong), PS4 (moderate), PM1 (moderate), PM2 (moderate), PP1 (supporting), and PP5 (supporting) meets the threshold for Pathogenic classification (1 Strong + 3 Moderate or 2 Strong).4
RET
Final classification
Likely Pathogenic
RET c.2410G>T · p.Val804Leu
RET
NM_020975.6:c.2410G>T (p.Val804Leu) is a missense variant in exon 14 of the RET gene, located in the tyrosine kinase domain.
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 strong, PS4 moderate, PM2 moderate, PP5 supporting; combination = 1 strong + 2 moderate + 1 supporting, which maps to Likely Pathogenic.
Classification rationale
PS3PS4PM2PP5
Likely Pathogenic
RET c.2410G>T
PS3 + PS4 + PM2 + PP5
→
Likely Pathogenic
Gene diagram
· NM_020975.6 · variants mapped to exon structure
RET
NM_020975.6
Fetching transcript structure from UCSC…
Applied criteria · 4 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 · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.308e-05; MAF= 0.00131%, 21/1605504 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000101812; MAF= 0.01018%, 3/29466 alleles, homozygotes = 0); grpmax FAF= 8.04e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.29923e-06; MAF= 0.00043%, 1/232600 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 5.24824e-05; MAF= 0.00525%, 1/19054 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0013%
· 21 / 1,605,504
0 hom · FAF 0.0008%
0 hom · FAF 0.0008%
Ashkenazi Jewish 3 / 29,466 |
0.01% |
European (Finnish) 1 / 60,942 |
0.0016% |
European (non-Finnish) 16 / 1,177,970 |
0.0014% |
South Asian 1 / 90,322 |
0.0011% |
+ 6 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, African/African American)
gnomAD v2.1
0.00043%
· 1 / 232,600
0 hom
0 hom
European (Finnish) 1 / 19,054 |
0.0052% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, 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 Pathogenic (18 clinical laboratories). (ClinVarID = 13946)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.715. BayesDel score = 0.337965.
Functional
Likely Oncogenic
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
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
Triaged references · 7 PMIDs not cited in assessment
15184865 ↗
Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors.
ONCOKB
9242375 ↗
Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain.
ONCOKB
10445857 ↗
Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma.
CLINVAR
10876191 ↗
Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation.
CLINVAR
11589684 ↗
Germline sequence variant S836S in the RET proto-oncogene is associated with low level predisposition to sporadic medullary thyroid carcinoma in the Spanish population.
CLINVAR
12694233 ↗
Segregation of the V804L mutation and S836S polymorphism of exon 14 of the RET gene in an extended kindred with familial medullary thyroid cancer.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR