Variant classification summary

NM_020975.6:c.2410G>A

RET · NP_066124.1:p.(Val804Met) · NM_020975.6

GRCh37: chr10:43614996 G>A · GRCh38: chr10:43119548 G>A

Gene: RET Transcript: NM_020975.6

Final call

VUS

PS3 strong PP3 supporting

Variant details

Gene

RET

Transcript

NM_020975.6

Protein

NP_066124.1:p.(Val804Met)

gnomAD AF

0.00012208004464641633 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: independent transformation and kinase assays show RET p.Val804Met is activating and functionally altered.

2

PP3 supporting: REVEL 0.716 exceeds the generic supporting threshold of 0.644.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one strong pathogenic criterion plus one supporting pathogenic criterion does not meet any likely pathogenic or pathogenic combination and no benign rule is satisfied, so the call is VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: reviewed reports document the exact GTG-to-ATG c.2410G>A change, but no different nucleotide change producing p.Val804Met was identified.	PMID:17047083 PMID:18299477 PMID:20719260
PS2	Not assessed	Not assessed: a ClinVar origin label says de novo, but confirmed maternity and paternity results are unavailable.	clinvar
PS3	Met	Met, strong: independent transformation and kinase assays show RET V804M alone is activating and functionally altered relative to wild-type RET.	PMID:17047083 PMID:17032739 PMID:32923848
PS4	Not met	Not met: no affected-versus-control counts or case frequency were reported, so the required OR >5.0 with 95% CI excluding 1.0 cannot be demonstrated.	PMID:18299477 PMID:20719260 PMID:20664475 gnomad_v4 gnomad_v2
PM1	Not assessed	Not assessed: Val804 is a kinase-domain gatekeeper, but comprehensive absence of benign variation in the relevant critical domain was not established.	PMID:17047083 PMID:32923848 hotspots cosmic
PM2	Not met	Not met: default all-comers grpmax FAF is 0.00010561 in gnomAD v4.1, exceeding the PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: RET-associated MEN2 is dominantly inherited, whereas PM3 applies only to recessive disorders with a pathogenic variant in trans.	PMID:17047083
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: V804L is reported for acquired inhibitor resistance, but no different missense change at residue 804 was established as pathogenic.	PMID:32923848 PMID:17047083 clinvar
PM6	Not assessed	Not assessed: a de novo origin label is present, but no case-level evidence supports an assumed de novo event.	clinvar
PP1	Not assessed	Not assessed: a 107-member V804M family is reported, but informative affected and unaffected meioses are not quantified.	PMID:20719260
PP2	Not assessed	Not assessed: RET missense disease mechanism is supported, but no gene-wide evidence established a low rate of benign missense variation.	PMID:17047083 oncokb gnomad_v4 clinvar
PP3	Met	Met at supporting: REVEL 0.716 exceeds the generic PP3 supporting threshold of >=0.644.	revel
PP4	Not assessed	Not assessed: the current patient's phenotype and family history are not sufficiently documented to determine whether they are highly specific for a single-gene disease.
PP5	Not met	Not met: ClinVar reports Pathogenic/Likely pathogenic laboratory submissions, but expert-panel submissions for the exact variant number 0.	clinvar
BA1	Not met	Not met: all-comers gnomAD grpmax FAF is 0.00010561, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest applicable all-comers grpmax FAF is 0.00012796, well below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but provides no verified healthy-adult observation qualifying for BS2.	gnomad_v2 gnomad_v4 PMID:18299477
BS3	Not met	Not met: available variant-specific assays show activating transformation and altered kinase behavior, not absence of a damaging effect on RET function.	PMID:17047083 PMID:17032739 PMID:32923848
BS4	Not assessed	Not assessed: no informative affected non-carriers or quantified non-segregation analysis is documented.	PMID:20719260
BP1	Not met	Not met: RET disease evidence supports activating missense variation, not a gene whose disease mechanism is primarily truncating variants.	PMID:17047083 oncokb clinvar
BP2	Not assessed	Not assessed: V804M is in cis with E805K, but E805K is not independently established as pathogenic, so the BP2 cis requirement remains unresolved.	PMID:17047083
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.716 is above the generic BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no alternate molecular basis for disease is documented for the case, so BP5 cannot be evaluated.
BP6	Not met	Not met: no benign expert-panel classification exists for the exact variant, while ClinVar laboratory submissions are Pathogenic or Likely pathogenic.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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