Variant classification summary

NM_020975.6:c.2428G>C

RET · NP_066124.1:p.(Gly810Arg) · NM_020975.6

GRCh37: chr10:43615014 G>C · GRCh38: chr10:43119566 G>C

Gene: RET Transcript: NM_020975.6

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

RET

Transcript

NM_020975.6

Protein

NP_066124.1:p.(Gly810Arg)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from the queried gnomAD datasets.

2

PP3 moderate: missense REVEL 0.809 exceeds the generic moderate threshold of 0.773.

Final determination: Under the generic ACMG/AMP 2015 fallback, one moderate and one supporting pathogenic criterion do not satisfy a likely pathogenic or pathogenic rule, and no benign rule is met; therefore 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 assessed	Not assessed: RET G810R is reported as an acquired somatic resistance mutation, not as a previously established pathogenic germline variant with an alternate nucleotide change.	PMID:31988000 spliceai
PS2	Not assessed	Not assessed: no documented affected proband, confirmed maternity and paternity, de novo result, and absence of family history are available.	PMID:31988000
PS3	Not met	Not met: RET G810R altered inhibitor sensitivity, but ATP affinity remained relatively close to wild type (Km 49.8 versus 15.3 μM), without demonstrating disease-relevant damaging RET activity.	PMID:31988000
PS4	Not assessed	Not assessed: no affected/control counts, odds ratio, or confidence interval were reported for RET c.2428G>C.	gnomad_v2 gnomad_v4 PMID:15604628 PMID:20301434 PMID:25810047 PMID:26389271 PMID:31988000
PM1	Not assessed	Not assessed: G810R lies in a reported RET solvent-front resistance region, but benign variation across that region has not been established and Cancer Hotspots found no significant hotspot.	PMID:31988000 hotspots
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, corresponding to observed frequency 0 versus the PM2 threshold <=0.0001.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: PM3 is restricted to recessive disorders, whereas the RET-associated MEN2 context is autosomal dominant.	PMID:11739416
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 assessed	Not assessed: other RET G810 substitutions are reported for acquired drug resistance, but no different missense change at residue 810 is established as pathogenic.	PMID:31988000
PM6	Not assessed	Not assessed: no affected-patient observation or assumed de novo report is documented, with or without parental confirmation.	PMID:31988000
PP1	Not assessed	Not assessed: no multiple affected relatives, informative meioses, or cosegregation data for RET c.2428G>C are documented.
PP2	Not assessed	Not assessed: no gene-level evidence establishes both low benign missense variation and missense variants as a common RET disease mechanism.
PP3	Met	Met at moderate strength: missense REVEL 0.809 meets the PP3 threshold of >=0.773.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history was provided to establish a highly specific RET-associated disease presentation.	clinvar PMID:15604628 PMID:11739416 PMID:25810047
PP5	Not met	Not met: ClinVar lists one exact-variant single-submitter uncertain-significance submission and zero expert-panel submissions.	clinvar PMID:15604628 PMID:11739416 PMID:25810047 PMID:31988000
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no grpmax FAF approaches the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF demonstrating frequency >=0.01 or excess over disease expectations.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: population records show absence, but provide no healthy adult genotype observation or phenotype and age data required for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no study demonstrated no damaging effect on RET function or splicing; available assays instead measured RET inhibitor resistance.	PMID:31988000
BS4	Not assessed	Not assessed: no affected relatives lacking the variant, pedigree, genotype data, or phenocopy evaluation are documented.
BP1	Not met	Not met: MEN2 is described as caused by activating germline RET mutations, not primarily by truncating variants.	PMID:11739416
BP2	Not assessed	Not assessed: no pathogenic second variant or cis/trans phase result is documented, and full penetrance is not established for the required dominant trans pathway.
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: missense REVEL 0.809 exceeds the BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no exact-variant case was documented with an alternate molecular basis for disease.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely-benign classification exists; the only submission is uncertain significance.	clinvar PMID:15604628 PMID:11739416 PMID:25810047
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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