Variant classification summary

NM_020975.5:c.1837C>A

RET · NP_066124.1:p.(Pro613Thr) · NM_020975.5

GRCh37: chr10:43609081 C>A · GRCh38: chr10:43113633 C>A

Gene: RET Transcript: NM_020975.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

RET

Transcript

NM_020975.5

Protein

NP_066124.1:p.(Pro613Thr)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

2

BP4 (Supporting): SpliceAI max delta 0.013 predicts no splice impact, below the 0.2 threshold.

3

Synthesis: with one supporting pathogenic (PM2) and one supporting benign (BP4) signal offsetting, the generic ACMG/AMP 2015 combination rules yield VUS.

Final determination: 1 supporting pathogenic criterion (PM2) plus 1 supporting benign criterion (BP4) does not meet any generic ACMG/AMP 2015 threshold for Pathogenic, Likely Pathogenic, Benign, or Likely Benign, so the variant is classified as 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: missense substitutions do not trigger null-variant mechanisms such as nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no independent pathogenic precedent for p.Pro613Thr from a different nucleotide change exists.	clinvar
PS2	Not assessed	Not assessed: no confirmed de novo occurrence with parental testing was documented.
PS3	Not assessed	Not assessed: no validated functional assay data for this variant was available.
PS4	Not assessed	Not assessed: no germline case series or case-control enrichment data was available for this variant.
PM1	Not assessed	Not assessed: no established RET domain or hotspot framework places codon 613 in a critical functional domain.
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no evidence of the variant in trans with a pathogenic variant was available.	generic_acmg_combination_rules
PM4	N/A	Not applicable: missense substitution causes no protein length change.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no pathogenic same-residue comparator (e.g., Pro613X) was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no presumed de novo occurrence was documented.
PP1	Not assessed	Not assessed: no informative relatives or segregation data were available.
PP2	Not assessed	Not assessed: no missense constraint data was available, and RET's mixed gain- and loss-of-function mechanisms preclude a generic call.
PP3	Not met	Not met: REVEL 0.319 sits in the indeterminate zone between the 0.290 and 0.644 thresholds.	revel bayesdel spliceai
PP4	Not assessed	Not assessed: no phenotype data establishing a RET-specific presentation was available.
PP5	Not assessed	Not assessed: no exact-variant ClinVar expert-panel pathogenic classification exists.	clinvar
BA1	Not met	Not met: absent from gnomAD, with no allele frequency reaching the stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: no allele frequency above the disease-prevalence threshold was observed.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no observations of the variant in healthy adults were available.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay data demonstrating wild-type-equivalent function was available.
BS4	Not assessed	Not assessed: no informative unaffected relatives or non-segregation data were available.
BP1	Not met	Not met: activating missense variants are a well-established disease mechanism in RET, so missense pathogenicity is common rather than rare.	oncokb pvs1_gene_context
BP2	Not assessed	Not assessed: no evidence of the variant in cis with a pathogenic variant was available.	generic_acmg_combination_rules
BP3	N/A	Not applicable: applies to in-frame indels in repetitive regions, not this missense substitution.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta 0.013 vs the 0.2 splice-impact threshold.	spliceai revel bayesdel
BP5	Not assessed	Not assessed: no established alternate molecular etiology was documented.
BP6	Not assessed	Not assessed: no exact-variant ClinVar expert-panel benign classification exists.	clinvar
BP7	N/A	Not applicable: applies to synonymous variants, not this missense substitution.	generic_acmg_combination_rules

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