RETc.2410G>TLikely pathogenic

Print report

Variant interpretation report

RET c.2410G>T, p.(Val804Leu)

NM_020975.6:c.2410G>T NP_066124.1:p.(Val804Leu) View identifiers

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.

About RET

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 moderate (pathogenic) · 4 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 18 Pathogenic
Pipeline record: 18 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PS3 (supporting): 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.
PM1 (moderate): 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.
PM2 (supporting): 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.
PM5 (supporting): 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.
PP1 (supporting): 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.

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: 5 Benign evidence criteria: 0

Pathogenic criteria applied · 5

PS3Supporting

PS3 · supporting

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.

PM1Moderate

PM1 · moderate

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.

PM2Supporting

PM2 · supporting

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.

PM5Supporting

PM5 · supporting

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.

PP1Supporting

PP1 · supporting

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.

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, PM5 supporting, PP1 supporting; combination = 1 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

21 / 1,605,504 alleles

gnomAD v4.1: 21 / 1,605,504 alleles. Recorded AF 1.308e-05. Recorded homozygote count 0.

gnomAD 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).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

18 reported laboratory submissions

18 Pathogenic.

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.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 5 met · 10 not met · 7 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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).

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.

PS3 (supporting): Functional studies directly characterized RET V804L among seven kinase domain mutations; the variant was introduced and biologically assessed (Iwashita et al., 1999).

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.

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.

PP1 (supporting): Co-segregation of V804L with familial medullary thyroid cancer in an extended kindred is reported in PMID:12694233.

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.

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.

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.

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.

Met · 5

PS3 SupportingFunctional 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. Details ▾Hide ▴

Evidence considered

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

Still missing

Full text of PMID:10445857 not available
abstract confirms variant-specific study but detailed experimental results (kinase activity
transformation assays
statistical measures) were not reviewed. PS3 strength could be upgraded to moderate or strong if full text demonstrates well-established functional evidence with multiple assay systems.
Additional functional studies (PMID:15184865 on V804 kinase inhibitor resistance
PMID:9242375) could strengthen PS3 if full texts confirm variant-specific data.

Sources

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

PM1 ModerateVal804 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. Details ▾Hide ▴

Evidence considered

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:10445857: Studies V804L among kinase domain mutations.
Multiple publications establish V804 as a MEN2/FMTC-associated residue.

Still missing

Automated hotspot analysis (somatic cancer-focused) flagged residue as not statistically significant
confirm that germline disease-associated hotspot methodology was applied appropriately.

Sources

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

PM2 SupportingThe 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=4.299×10⁻⁶ (1/232
600 exomes
0 homozygotes).
gnomAD v4.1: AF=1.308×10⁻⁵ (21/1
605
504 alleles
0 homozygotes)
grpmax FAF=8.04×10⁻⁶.
gnomAD-Canada v1.0: absent.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PM5 SupportingNM_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. Details ▾Hide ▴

Evidence considered

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').

Still missing

Automated PM5 candidate harvesting did not identify comparators (pm5_candidates.json: 'Unable to confirm classic same-residue PM5 semantics safely'). Manual review confirms V804M qualifies. Confirm V804M ClinVar classification status for formal PM5 application.

Sources

PMID:10876191 ↗

PP1 SupportingCo-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. Details ▾Hide ▴

Evidence considered

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

Still missing

Full text of PMID:12694233 not available
abstract confirms extended kindred segregation but does not detail number of meioses or affected/unaffected counts. PP1 strength could be upgraded with full-text confirmation.

Sources

PMID:12694233 ↗

Not met · 10 · evaluated, threshold not reached

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. RET has observable benign missense variation in population databases (gnomAD), and the gene's missense Z-score is not sufficiently extreme to meet the low benign missense rate requirement of PP2. Details ▾Hide ▴

Evidence considered

RET is a commonly sequenced gene with observable missense variation in gnomAD.
Gain-of-function missense variants are the established MEN2 mechanism
but benign missense constraint is not sufficiently established.

Still missing

RET missense constraint metrics (Z-score
pLI
missense o/e) could be formally reviewed for a definitive PP2 determination.

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP3 In silico evidence is mixed and does not meet the threshold for multiple lines of computational support for a deleterious effect. REVEL score 0.715 leans pathogenic but is below the strong pathogenic range (≥0.9). BayesDel score 0.338 does not support pathogenicity (leans benign). SpliceAI max delta 0.01 predicts no splicing impact. Only one of three computational tools supports a deleterious effect. Details ▾Hide ▴

Evidence considered

REVEL: 0.715 (moderately elevated
pathogenic-leaning).
BayesDel: 0.338 (benign-leaning
below typical pathogenic threshold).
SpliceAI: max delta 0.01 (no predicted splice impact).
HCI prior: not available for RET.

Sources

revelbayesdelspliceai ↗

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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=4.299×10⁻⁶.
gnomAD v4.1: AF=1.308×10⁻⁵.

Sources

gnomad_v2 ↗gnomad_v4 ↗

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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 max subpop AF: 5.248×10⁻⁵ (Finnish).
gnomAD v4.1 max subpop AF: 1.018×10⁻⁴ (Ashkenazi Jewish).
Both far below 0.3% BS1 threshold.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 RET-MEN2/FMTC is an autosomal dominant disorder with high penetrance. Only 1 allele was observed in gnomAD v2.1 and 21 in v4.1. A single observation cannot establish that the variant is observed in healthy adults without disease, especially given the late-onset and variable expressivity of MEN2/FMTC. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 1/232
600 alleles
cannot establish healthy adult observation.
gnomAD v4.1: 21/1
605
504 alleles
gnomAD does not provide phenotype data to confirm unaffected status.

Still missing

Phenotype data for gnomAD allele carriers is unavailable.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 Available functional evidence supports a damaging effect, not a benign effect. PMID:10445857 studied V804L among kinase domain mutations and the variant is consistently associated with MEN2/FMTC in clinical and functional literature. BS3 requires well-established functional studies showing no damaging effect. Details ▾Hide ▴

Evidence considered

PMID:10445857: Functional characterization of V804L among kinase domain mutations
evidence points toward damaging effect consistent with MEN2/FMTC pathogenesis.
OncoKB classifies as 'Likely Oncogenic' with gain-of-function effect.

Sources

PMID:10445857 ↗

BS4 Available segregation evidence supports co-segregation with disease, not lack of segregation. PMID:12694233 reports segregation of V804L with FMTC in an extended kindred. BS4 requires lack of co-segregation in affected family members. Details ▾Hide ▴

Evidence considered

PMID:12694233: Reports co-segregation of V804L with FMTC in extended kindred (supports pathogenicity
not benign).

Sources

PMID:12694233 ↗

BP1 RET disease mechanism in MEN2/FMTC is primarily gain-of-function missense variants, not truncating variants. BP1 applies when a gene's disease mechanism is primarily through truncating variants and the observed variant is missense. The opposite is true for RET — missense variants are the established pathogenic mechanism. Details ▾Hide ▴

Evidence considered

RET-MEN2/FMTC is caused by gain-of-function missense mutations
truncating variants are not the primary disease mechanism.

BP4 Multiple lines of computational evidence do not consistently support a benign effect. REVEL 0.715 predicts a deleterious effect. BayesDel 0.338 does not strongly indicate benign. SpliceAI shows no splice impact. The in silico evidence is mixed and does not meet the BP4 threshold requiring multiple lines of computational evidence supporting no impact. Details ▾Hide ▴

Evidence considered

REVEL: 0.715 (deleterious prediction
contradicts benign).
BayesDel: 0.338 (does not strongly support benign).
SpliceAI: max delta 0.01 (no splice impact
neutral).

Sources

revelbayesdelspliceai ↗

BP6 ClinVar reports this variant as Pathogenic by 18 clinical laboratories. No reputable source reports it as benign. BP6 requires a reputable source to report the variant as benign with inaccessible evidence. Details ▾Hide ▴

Evidence considered

ClinVar classification: Pathogenic (18 clinical laboratories). No benign reports.

Sources

clinvar ↗

Not assessed · 7 · no assessment recorded

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

Evidence considered

No alternative nucleotide substitution at c.2410 with confirmed pathogenicity found in ClinVar or literature.

Still missing

ClinVar search for other nucleotide changes at NM_020975.6:c.2410 could identify PS1 candidates.

PS2 No de novo report for NM_020975.6:c.2410G>T was identified in the literature reviewed. PM6/PS2 require a confirmed de novo observation with maternity and paternity confirmation. Details ▾Hide ▴

Evidence considered

No de novo report found.

Still missing

De novo occurrence data not available in source materials.

Sources

PMID:10445857 ↗PMID:10876191 ↗PMID:11589684 ↗PMID:12694233 ↗PMID:15184865 ↗PMID:9242375 ↗

PS4 Insufficient statistical case-control data to meet PS4 threshold. While this variant is reported by 18 clinical laboratories in ClinVar as Pathogenic and appears in multiple clinical/familial contexts, specific proband counts, case-control statistics, and odds ratios are not available in the evidence sources reviewed. PS4 requires PM2 first (met) plus statistically significant enrichment in affected individuals versus controls. Details ▾Hide ▴

Evidence considered

ClinVar: Pathogenic classification by 18 clinical laboratories (ClinVarID 13946).
PMID:10235148: Family with germline RET V804L and pheochromocytomas.
PMID:12694233: Extended kindred with V804L and FMTC.

Still missing

Proband counts from clinical laboratories are needed to compute odds ratios.
Case-control data not extractable from available evidence sources.

Sources

clinvar ↗PMID:12694233 ↗

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

Evidence considered

No de novo report found.

Still missing

De novo data not available in source materials.

Sources

PMID:10445857 ↗PMID:11589684 ↗PMID:12694233 ↗

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. Details ▾Hide ▴

Evidence considered

Patient phenotype data not available in case materials. MEN2/FMTC phenotype is associated with RET mutations
but without specific clinical presentation details PP4 cannot be formally adjudicated.

Still missing

Patient phenotype and family history details required for PP4 assessment.

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. Details ▾Hide ▴

Evidence considered

No cis/trans phase data available in evidence sources.

Still missing

Phase data unavailable.

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. Details ▾Hide ▴

Evidence considered

No alternate molecular diagnosis data available.

Still missing

Patient-level alternate diagnosis data unavailable.

Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANM_020975.6:c.2410G>T (p.Val804Leu) is a missense substitution. PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites). The variant does not fall into any PVS1 bucket per ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴

Evidence considered

Missense substitution
variant_bucket=other per PVS1_variant_assessment.

PP5 N/AIndependent evaluation of available evidence is being performed. ClinVar reports this variant as Pathogenic by 18 clinical laboratories, but the evidence is accessible for independent assessment. PP5 is reserved for situations where reputable sources report the variant as pathogenic but the evidence is not available for independent evaluation. Details ▾Hide ▴

Evidence considered

ClinVar classification is available for independent review
evidence sources are accessible.

BP7 N/ANM_020975.6:c.2410G>T (p.Val804Leu) is a missense variant, not synonymous. BP7 applies only to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. Details ▾Hide ▴

No further detail was recorded.

PS5 N/AIndependent evaluation of available evidence is being performed, making PS5 (reputable source reports as pathogenic without available evidence) not applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: RET
Transcript: NM_020975.6
Coding (HGVS c.): NM_020975.6:c.2410G>T
Protein (HGVS p.): NP_066124.1:p.(Val804Leu)
GRCh38: chr10:43119548 G>T
GRCh37: chr10:43614996 G>T
ClinVar: 13946, 3893813, 38613

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

—

Strand

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Variants mapped

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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 21 / 1,605,504 alleles AF 1.31e-05 · 0 homozygotes · FAF 8.04e-06

gnomAD v2.1 1 / 232,600 alleles AF 4.3e-06 · 0 homozygotes

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.3e-05 · 21 / 1,605,504 alleles · 0 hom · FAF 8e-06

Ashkenazi Jewish3 / 29,466	0.0001
European (Finnish)1 / 60,942	1.6e-05
European (non-Finnish)16 / 1,177,970	1.4e-05
South Asian1 / 90,322	1.1e-05

0 alternate alleles recorded in 6 other groups: Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, African/African American.

gnomAD v2.1

AF 4.3e-06 · 1 / 232,600 alleles · 0 hom

European (Finnish)1 / 19,054

5.2e-05

0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD 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.

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -39 bp

0.010

SpliceAI acceptor gainat +162 bp

0.010

SpliceAI donor lossat -187 bp

0.010

SpliceAI donor gainat +4 bp

0.000

Pangolin splice lossmagnitude shown

-0.030

Pangolin splice gain

0.010

Other predictors

REVEL: 0.715
BayesDel: 0.338

How the predictions were used

Evidence considered

REVEL: 0.715 (moderately elevated
pathogenic-leaning).
BayesDel: 0.338 (benign-leaning
below typical pathogenic threshold).
SpliceAI: max delta 0.01 (no predicted splice impact).
HCI prior: not available for RET.

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL: 0.715 (deleterious prediction
contradicts benign).
BayesDel: 0.338 (does not strongly support benign).
SpliceAI: max delta 0.01 (no splice impact
neutral).

Sources

revelbayesdelspliceai ↗

No further detail was recorded.

Statement

In silico

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

7 paper records listed. 4 cited in the classification.

Cited in the classification

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

Iwashita T et al. · 1999 Jul 1

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.
→ PS3 → PM1 Names this variant
PMID 10445857 ↗
Source detail

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.

Feldman GL et al. · 2000 Jul

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.
→ PM5 Does not name this variant
PMID 10876191 ↗
Source detail

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.

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.
→ PM1 → PP1 Names this variant
PMID 12694233 ↗
Source detail

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.

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.
→ PS3 → PM1 Names this variant
PMID 15184865 ↗
Source detail

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.

Other recorded publications

Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain.

Reports oncogenic activation of RET by two distinct FMTC mutations (V804M and V806M, originally described as GTG→ATG and GTG→TTG substitutions) affecting the tyrosine kinase domain. NM_020975.6:c.2410G>T (V804L) was not specifically identified in the abstract; the paper focuses on V804M and V806M.
Does not name this variant
PMID 9242375 ↗
Quoted passage
Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain.
Abstract: discusses two FMTC mutations in tyrosine kinase domain. Title: 'Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain.'
Germline sequence variant S836S in the RET proto-oncogene is associated with low level predisposition to sporadic medullary thyroid carcinoma in the Spanish population.

Case-control study of the RET S836S (c.2439C>T, exon 14) polymorphism and its association with sporadic medullary thyroid carcinoma in the Spanish population. Reports S836S allele frequency of 9.3% in MTC cases vs 3.6% in controls. NM_020975.6:c.2410G>T (V804L) was not identified in this paper.
Does not name this variant
PMID 11589684 ↗
Quoted passage
Recently, over-representation of a germline polymorphic sequence variant located within exon 14 of the RET proto-oncogene at codon 836 (nt c.2439C to T, S836S) was found to be associated with sporadic MTC.
Full text reviewed; variant not found. Paper exclusively discusses S836S (c.2439C>T).
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a methodological paper describing the Sherloc classification framework, not a variant-specific study. NM_020975.6:c.2410G>T (V804L) was not discussed.
Does not name this variant
PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 21 / 1,605,504 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗

ClinVar 18 Pathogenic 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.