RET

Final classification

Likely Pathogenic

RET c.2410G>T · p.Val804Leu

RET

NM_020975.6:c.2410G>T (p.Val804Leu) in RET is classified as Likely Pathogenic using generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868).

Gene

RET

Transcript

NM_020975.6

HGVS · transcript:coding

NM_020975.6:c.2410G>T

Consequence

N/A

GRCh38

chr10:43119548 G>T

GRCh37

chr10:43614996 G>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: PS3 supporting, PM1 moderate, PM2 supporting, PM5 supporting, PP1 supporting; combination = 1 moderate + 4 supporting, which maps to 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, PM5 supporting, PP1 supporting; combination = 1 moderate + 4 supporting, which maps to Likely Pathogenic.

Classification rationale

PS3PM1PM2PM5PP1 Likely Pathogenic

RET c.2410G>T

NM_020975.6:c.2410G>T (p.Val804Leu) in RET is classified as Likely Pathogenic using generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868).¹ PM1 (moderate): Val804 is in the RET tyrosine kinase domain, a critical functional domain where MEN2/FMTC-associated missense mutations cluster. Multiple publications identify codon 804 as a disease-associated residue.² PS3 (supporting): Functional studies directly characterized RET V804L among seven kinase domain mutations; the variant was introduced and biologically assessed (Iwashita et al., 1999).³ PM2 (supporting): Extremely low allele frequency in population databases. gnomAD v2.1 AF=4.3×10⁻⁶ (1/232,600); gnomAD v4.1 AF=1.3×10⁻⁵ (21/1,605,504); absent from gnomAD-Canada.⁴ PM5 (supporting): V804M (c.2410G>A) is a well-established pathogenic variant at the same residue, reported as FMTC-causing in PMID:10876191. Per ACMG/AMP PM5, a novel missense at a residue with a known pathogenic missense change provides supporting evidence.⁵ PP1 (supporting): Co-segregation of V804L with familial medullary thyroid cancer in an extended kindred is reported in PMID:12694233.⁶ Overall: 1 moderate (PM1) + 4 supporting (PS3, PM2, PM5, PP1) criteria met. This satisfies the '1 Moderate and 4 Supporting' Likely Pathogenic combination under generic ACMG/AMP 2015 rules.⁷ No benign criteria were met. BA1 (AF>1%): not met. BS1 (AF>0.3%): not met. BS3 (functional evidence of no damage): not met — available functional evidence supports damaging effect.⁸ ClinVar consensus supports pathogenicity: 18 clinical laboratories classify as Pathogenic (ClinVar Variation ID: 13946), though most submissions are single-submitter review status without expert panel review.⁹ Several criteria require human review: PS3 strength may be upgradable with full-text review of PMID:10445857 and PMID:15184865; PP1 strength may be upgradable with full-text segregation data; PM1 should be confirmed against germline-specific hotspot methodology.¹⁰

PS3 + PM1 + PM2 + PM5 + PP1 → Likely Pathogenic

1 generic_acmg_combination_rules

2 PMID:15184865 ↗PMID:9242375 ↗PMID:10445857 ↗PMID:12694233 ↗

3 PMID:10445857 ↗

4 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

5 PMID:10876191 ↗

6 PMID:12694233 ↗

7 generic_acmg_combination_rules

8 gnomad_v2 ↗gnomad_v4 ↗PMID:10445857 ↗

9 clinvar ↗

10 PMID:10445857 ↗PMID:15184865 ↗PMID:12694233 ↗

Gene diagram · NM_020975.6 · variants mapped to exon structure

RET NM_020975.6

Fetching transcript structure from UCSC…

Applied criteria · 5 applied · 17 assessed

Applied · 5

Strength Supporting Moderate Strong Very strong

✓

PS3 supporting review Pathogenic

Functional characterization of V804L was performed in PMID:10445857 (Iwashita et al., 1999). The study introduced seven RET kinase domain mutations including V804L and assessed their biological and biochemical properties. The abstract confirms V804L was directly studied. This provides variant-specific functional evidence supporting a deleterious effect, consistent with the known gain-of-function mechanism of RET kinase domain mutations in MEN2/FMTC.

PMID:10445857 (Iwashita et al.1999): Direct functional study of RET V804L among seven kinase domain mutationsvariant introduced and biologically characterized. Abstract confirms 'valine 804→leucine (V804L)' was one of the mutations introduced into Ret.

PMID:10445857 ↗

✓

PM1 moderate review Pathogenic

Val804 is located in the RET tyrosine kinase domain (codons 724–1010), a critical and well-established functional domain. Multiple independent publications identify codon 804 as a disease-associated residue in MEN2 and FMTC (PMID:15184865, PMID:9242375, PMID:10445857, PMID:10235148, PMID:12694233). The automated hotspot analysis flagged this residue as not statistically significant in somatic cancer, but this does not diminish the established role of RET kinase domain residues in germline MEN2/FMTC predisposition. No benign missense variation is observed at this specific residue in gnomAD.

V804 is in the RET tyrosine kinase domain (critical functional domain for kinase activity).PMID:15184865: Title explicitly references 'disease associated mutations at valine 804 in the RET receptor tyrosine kinase.'PMID:9242375: Studies FMTC mutations affecting the tyrosine kinase domain.

PMID:15184865 ↗PMID:9242375 ↗PMID:10445857 ↗PMID:12694233 ↗

✓

PM2 supporting Pathogenic

The variant is extremely rare in population databases. gnomAD v2.1: 1/232,600 alleles (AF=4.3×10⁻⁶). gnomAD v4.1: 21/1,605,504 alleles (AF=1.3×10⁻⁵; grpmax FAF=8.04×10⁻⁶). Both are well below the 0.1% PM2 threshold for non-VCEP frameworks. Absent from gnomAD-Canada v1.0. No homozygotes observed.

gnomAD v2.1: AF=4.299×10⁻⁶ (1/232600 exomes0 homozygotes).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PM5 supporting review Pathogenic

NM_020975.6:c.2410G>A (p.Val804Met, V804M) is a well-established pathogenic variant at the same amino acid residue. PMID:10876191 (Feldman et al., 2000) reports a family with FMTC due to the RET V804M mutation. V804M is classified as Pathogenic in ClinVar. Per ACMG/AMP PM5, a novel missense change at an amino acid residue where a different missense change has been determined to be pathogenic can be applied as supporting evidence.

V804M (c.2410G>A) is a known pathogenic variant at the same codon 804.PMID:10876191 confirms V804M as FMTC-causing (title: 'Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG→ATG) mutation').

PMID:10876191 ↗

✓

PP1 supporting review Pathogenic

Co-segregation of the V804L mutation with familial medullary thyroid cancer (FMTC) was demonstrated in an extended kindred as reported in PMID:12694233. The title and abstract confirm 'Segregation of the V804L mutation... in an extended kindred with familial medullary thyroid cancer.' This provides evidence of co-segregation with disease in a gene definitively known to cause MEN2/FMTC.

PMID:12694233 (Borrego et al.): Co-segregation of RET V804L with FMTC in an extended kindred confirmed by abstract.

PMID:12694233 ↗

Assessed · not applied

Pathogenic

PS1 No evidence of a different nucleotide change at the same position (c.2410) with independently established pathogenicity was identified.

PS2 No de novo report for NM_020975.6:c.2410G>T was identified in the literature reviewed.

PS4 Insufficient statistical case-control data to meet PS4 threshold.

PM6 No de novo observation for NM_020975.6:c.2410G>T with confirmed maternity and paternity was identified in the reviewed literature.

PP2 While RET missense variants are a well-established mechanism of disease in MEN2/FMTC (gain-of-function), PP2 also requires a low rate of benign missense variation in the gene.

PP3 In silico evidence is mixed and does not meet the threshold for multiple lines of computational support for a deleterious effect.

PP4 Insufficient patient-specific phenotype data available in the evidence sources to determine whether the patient's phenotype or family history is highly specific for MEN2/FMTC with a single genetic etiology.

Benign

BA1 The variant has an allele frequency of ~4.3×10⁻⁶ in gnomAD v2.1 and 1.3×10⁻⁵ in gnomAD v4.1, far below the 1% BA1 threshold.

BS1 Maximum subpopulation allele frequency is 5.2×10⁻⁵ in European (Finnish) in gnomAD v2.1 and 1.0×10⁻⁴ in Ashkenazi Jewish in gnomAD v4.1, both well below the 0.3% BS1 threshold.

BS2 RET-MEN2/FMTC is an autosomal dominant disorder with high penetrance.

BS3 Available functional evidence supports a damaging effect, not a benign effect.

BS4 Available segregation evidence supports co-segregation with disease, not lack of segregation.

BP1 RET disease mechanism in MEN2/FMTC is primarily gain-of-function missense variants, not truncating variants.

BP2 No phase information is available to determine whether this variant has been observed in trans with a pathogenic RET variant (relevant for fully penetrant dominant disorders) or in cis with a pathogenic variant in any inheritance pattern.

BP4 Multiple lines of computational evidence do not consistently support a benign effect.

BP5 No evidence that this variant was observed in a case with a definitive alternate molecular basis for disease was identified in the reviewed materials.

BP6 ClinVar reports this variant as Pathogenic by 18 clinical laboratories.

N/A · 3 PVS1 · PP5 · BP7

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%

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

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

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (18 clinical laboratories). (ClinVarID = 13946)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.715. BayesDel score = 0.337965.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

9papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 3 further PMIDs triaged but not cited — see Sources & References.

Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma.

PMID 10445857 ↗ · Iwashita T et al. · 1999 Jul 1 CLINVAR · functional

Searched

c.2410G>Tp.Val804LeuV804Lvaline 804

Found

Seven RET kinase domain mutations including V804L were introduced into Ret and biologically characterized. The study assessed the biological and biochemical properties of RET kinase domain mutants, confirming that V804L was among the directly studied variants.

Variant

✓ Names this variant

Applied to

→PM1 supports · met →PS3 supports · met

Why

Variant-specific functional data confirmed. Referenced in PS3 assessment at supporting strength; full-text review recommended for possible PS3 upgrade.

We introduced seven mutations (glutamic acid 768→aspartic acid (E768D), valine 804→leucine (V804L), alanine 883→phenylalanine (A883F), serine 891→alanine (S891A), methionine 918→threonine (M918T), glutamic acid 921→lysine (E921K), and asparagine 922→lysine (N922K)) into Ret.

Location Abstract: 'We introduced seven mutations (glutamic acid 768→aspartic acid (E768D), valine 804→leucine (V804L), alanine 883→phenylalanine (A883F)...).' · Context In vitro mutagenesis and functional characterization of RET kinase domain mutants; specific assay types not detailed in abstract.

Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation.

PMID 10876191 ↗ · Feldman GL et al. · 2000 Jul CLINVAR · functional

Searched

c.2410G>Tp.Val804LeuV804Lvaline 804 leucine

Found

Reports a germline RET V804M (GTG→ATG) mutation causing familial medullary thyroid carcinoma in two families. This paper discusses the V804M variant at the same codon but does not study V804L. NM_020975.6:c.2410G>T (V804L) was not identified in this paper.

Variant

◇ Residue / gene-level — variant not named

Applied to

→PM5 supports · met

Why

Variant not identified; V804M confirmed as pathogenic at same residue. Referenced in PM5 assessment as comparator evidence.

Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation.

Location Abstract: describes V804M (GTG→ATG) mutation in exon 14 of RET.

Segregation of the V804L mutation and S836S polymorphism of exon 14 of the RET gene in an extended kindred with familial medullary thyroid cancer.

PMID 12694233 ↗ CLINVAR · segregation

Searched

c.2410G>Tp.Val804LeuV804Lsegregation V804L

Found

Co-segregation of the V804L mutation with familial medullary thyroid cancer demonstrated in an extended kindred. The paper also analyzes the S836S polymorphism in the same family. This provides segregation evidence for V804L in FMTC.

Variant

✓ Names this variant

Applied to

→PM1 supports · met →PP1 supports · met

Why

Variant-specific segregation confirmed in extended kindred. Referenced in PP1 assessment at supporting strength; full-text review recommended for upgrade assessment.

Segregation of the V804L mutation and S836S polymorphism of exon 14 of the RET gene in an extended kindred with familial medullary thyroid cancer.

Location Title: 'Segregation of the V804L mutation and S836S polymorphism of exon 14 of the RET gene in an extended kindred with familial medullary thyroid cancer.'

Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors.

PMID 15184865 ↗ ONCOKB · functional

Searched

c.2410G>Tp.Val804LeuV804Lvaline 804

Found

Disease-associated mutations at RET valine 804 (including V804L and V804M) were found to confer resistance to selective kinase inhibitors (PP1, PP2, ZD6474). The paper demonstrates that V804 mutations alter drug sensitivity, confirming functional significance of this residue.

Variant

✓ Names this variant

Applied to

→PM1 supports · met →PS3 supports · met

Why

V804 residue functional significance confirmed. Referenced in PM1 assessment; could support PS3 upgrade if full text confirms direct V804L functional data.

Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors.

Location Title and abstract: 'Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors.' Abstract snippet confirms V804 mutations studied. · Context Kinase inhibitor sensitivity assays (PP1, PP2, ZD6474) against oncogenic RET kinase mutants.

PMID PMID:10445857

PMID PMID:10445857 ↗

Found