NM_020975.6:c.1783G>A

RET · NP_066124.1:p.(Glu595Lys) · NM_020975.6

GRCh37: chr10:43609027 G>A · GRCh38: chr10:43113579 G>A

Gene: RET Transcript: NM_020975.6

Final call

VUS

PM2 supporting

Variant details

Gene

RET

Transcript

NM_020975.6

Protein

NP_066124.1:p.(Glu595Lys)

gnomAD AF

1.8631087086669332e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): ultra-rare in population databases — gnomAD v4.1 total AF 1.86e-06 (max subpopulation 0.00336%, 0 homozygotes), below the <0.1% PM2 threshold.

Overall classification: VUS — the single supporting criterion satisfies no Likely Pathogenic or Pathogenic combination under generic ACMG/AMP 2015 (PMID:25741868).

Final determination: Under the generic ACMG/AMP 2015 combination rules (fallback for the absent RET VCEP/CSpec framework), a single supporting pathogenic criterion (PM2) meets no pathogenic or benign combination threshold, so the variant is classified as Variant of Uncertain Significance.

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: this missense substitution is not a null variant (nonsense, frameshift, or canonical splice), so PVS1's structural prerequisite is absent.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: no alternate nucleotide change can produce p.Glu595Lys (GAG>AAG is the only one), and the change is not an established pathogenic variant.	PMID:25741868 pm5_candidates clinvar oncokb
PS2	Not assessed	Not assessed: no de novo occurrence, proband data, or parental testing was available for this variant.
PS3	Not met	Not met: no functional studies exist for p.Glu595Lys; OncoKB classifies E595K as 'Unknown Oncogenic Effect' with no variant-specific functional evidence.	clinvar oncokb PMID:25741868 PMID:35534704
PS4	Not assessed	Not assessed: no case-control or cohort data exist for this exact variant, which is absent even from the only validated cohort paper (PMID:35534704).	clinvar PMID:35534704
PM1	Not met	Not met: p.Glu595 is not in a mutational hotspot — absent from CancerHotspots.org, and the established MEN2 cysteine hotspots (C609-C634) exclude it.	PMID:25741868 oncokb clinvar
PM2	Met	Met (supporting): ultra-rare in population databases — gnomAD v4.1 total AF 1.86e-06 (max subpopulation 0.00336%, 0 homozygotes), below the <0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada clinvar
PM3	N/A	Not applicable: RET germline disease here is autosomal dominant with a gain-of-function mechanism, so the recessive in-trans criterion does not apply.	PMID:25741868 clinvar
PM4	N/A	Not applicable: the missense substitution does not change protein length, so PM4 (in-frame indels, stop-loss) has nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no pathogenic alternate missense change at Glu595 (e.g., E595Q/E595A) has been reported for comparison.	pm5_candidates PMID:25741868 clinvar
PM6	Not assessed	Not assessed: no evidence of a de novo event — no proband data, parental testing, or de novo report exists for this variant.
PP1	Not assessed	Not assessed: no segregation data exist — no pedigree, affected-relative genotyping, or segregation report for this variant.
PP2	Not assessed	Not assessed: no missense constraint data (e.g., gnomAD missense Z-score) was available to confirm a low rate of benign RET missense variation.	PMID:25741868 oncokb
PP3	Not met	Not met: BayesDel 0.197 is the only pathogenic-leaning score; REVEL 0.47 is indeterminate and SpliceAI max delta 0.00 shows no splice impact, so multiple lines of support are lacking.	spliceai revel bayesdel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no case-level phenotype documentation exists; the ClinVar record-level conditions are asserted labels with no documented carrier phenotype.	clinvar PMID:35534704 PMID:15604628
PP5	Not met	Not met: no ClinVar expert-panel classification exists for this exact variant (0 expert-panel submissions, 2-star review), so the PP5 trigger is absent.	clinvar
BA1	Not met	Not met: maximum allele frequency 0.00336% is more than 300-fold below the >5% BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: gnomAD v4.1 total AF 0.00019% is ~90-fold below the >0.3% BS1 threshold, and frequency is not greater than expected for MEN2.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD carriers (1-3 heterozygous, 0 homozygotes) lack phenotype or age data, so a healthy-adult status with full penetrance cannot be established.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: no functional studies exist to show a lack of damaging effect; SpliceAI's delta 0.00 is an in-silico prediction, not a functional assay.	clinvar oncokb spliceai PMID:25741868 PMID:35534704
BS4	Not assessed	Not assessed: no family studies exist — no non-segregation observations (unaffected carriers or affected non-carriers) for this variant.
BP1	Not met	Not met: RET is not primarily a truncating-disease gene — germline missense gain-of-function variants are a primary MEN2/FMTC mechanism.	PMID:25741868 oncokb clinvar
BP2	Not met	Not met: no cis- or trans-phase observation of this variant with a pathogenic variant was reported.	PMID:25741868 clinvar
BP3	N/A	Not applicable: the missense substitution is not an in-frame indel in a repetitive region, so BP3 has nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: only SpliceAI (max delta 0.00) supports no impact; REVEL 0.47 is indeterminate and BayesDel 0.197 is pathogenic-leaning, failing the multiple-lines requirement.	spliceai revel bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no case-level data document an alternate molecular basis of disease in a carrier of this variant.	clinvar PMID:35534704
BP6	Not met	Not met: no ClinVar expert-panel benign classification exists for this exact variant (0 expert-panel submissions), so the BP6 trigger is absent.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants; this missense substitution alters the encoded protein sequence.	generic_acmg_combination_rules

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