LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-11
Case ID: NM_020975.6_c.2944C_T_20261011_003835
Framework: ACMG/AMP 2015
Variant classification summary

NM_020975.6:c.2944C>T

RET  · NP_066124.1:p.(Arg982Cys)  · NM_020975.6
GRCh37: chr10:43620335 C>T  ·  GRCh38: chr10:43124887 C>T
Gene: RET Transcript: NM_020975.6
Final call
Likely Benign
BS1 strong BS2 supporting BS3 supporting BP2 supporting BP4 supporting BP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
RET
Transcript
NM_020975.6
Protein
NP_066124.1:p.(Arg982Cys)
gnomAD AF
0.016363314153572752 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BS1 (strong) because allele frequencies exceed 0.01.
2
Likely Benign: BS2 (supporting) because gnomAD reports 372 homozygotes.
3
Likely Benign: BS3 (supporting) because R982C alone did not alter GDNF-dependent MAPK activity.
4
Likely Benign: BP2 (supporting) because R982C was observed in trans with pathogenic p.C634Y.
5
Likely Benign: BP4 (supporting) because REVEL is 0.282, below the calibrated benign threshold.
6
Likely Benign: BP5 (supporting) because affected individuals carried R982C with alternate RET variants.
Final determination: Under the generic ACMG/AMP 2015 fallback, one strong benign criterion plus at least one supporting benign criterion yields Likely Benign.
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 PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_020975.6:c.2944C>T in RET is a missense substitution predicted to produce NP_066124.1:p.(Arg982Cys). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: no distinct nucleotide change producing the same p.Arg982Cys substitution is established as pathogenic; the queried R982C itself is reported as benign or uncertain.
PMID:14633923 PMID:15741265 PMID:21655256 PMID:22729463
PS2 Not met Not met: reported familial observations document maternal or paternal inheritance, with no confirmed de novo RET c.2944C>T event.
PMID:14633923 PMID:21655256 PMID:22729463
PS3 Not met Not met: R982C alone did not alter GDNF-dependent MAPK activity, while near-complete loss occurred only with the paired G691S/R982C construct.
PMID:22729463 PMID:21655256 PMID:15741265
PS4 Not met Not met: R982C occurred in 3/84 Hirschsprung cases versus 0/96 controls, but confounding variants and population frequency prevent convincing disease-specific enrichment.
PMID:14633923 gnomad_v4
PM1 Not met Not met: despite kinase-domain location, R982C has gnomAD v4.1 AF 0.0163633 and grpmax FAF 0.04122125, with no statistically significant hotspot evidence.
gnomad_v4 PMID:22837065
PM2 Not met Not met: gnomAD v4.1 total allele frequency is 0.0163633, far above the PM2 threshold of 0.0001.
gnomad_v2 gnomad_v4
PM3 N/A Not applicable: available RET evidence does not establish a recessive disorder or a biallelic affected individual with the variant demonstrably in trans.
PM4 N/A PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_020975.6:c.2944C>T in RET is a missense substitution predicted to produce NP_066124.1:p.(Arg982Cys). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not met Not met: zero same-residue comparator candidates were identified, and no alternate missense change at Arg982 is established as pathogenic.
PMID:14633923 PMID:15741265 PMID:21655256 PMID:22729463
PM6 Not met Not met: available reports show maternal or paternal transmission rather than an assumed de novo occurrence without parental testing.
PMID:14633923 PMID:21655256 PMID:22729463
PP1 Not met Not met: transmission is reported, but informative affected-relative cosegregation with the disease phenotype is not established.
PMID:14633923 PMID:21655256 PMID:22729463
PP2 Not met Not met: benign missense variation is common in RET, with R982C at gnomAD v4.1 AF 0.0163633 and grpmax FAF 0.04122125.
gnomad_v4 PMID:14633923 PMID:21655256
PP3 Not met Not met: REVEL 0.282 is below the >=0.644 PP3 supporting threshold from the ClinGen SVI calibration.
revel
PP4 Not met Not met: reported phenotypes are heterogeneous and often involve additional RET variants, with no distinctive phenotype uniquely attributable to R982C.
PMID:14633923 PMID:21655256 PMID:22729463
PP5 Not met Not met: ClinVar has zero expert-panel submissions for exact R982C, so laboratory and aggregate classifications cannot trigger PP5.
clinvar
BA1 Not met Not met: the highest observed allele frequency is 0.0431147, below the generic BA1 threshold of 0.05.
gnomad_v2 gnomad_v4
BS1 Met Met, strong: gnomAD total allele frequencies of 0.0185349 and 0.0163633 exceed the generic BS1 threshold of 0.01.
gnomad_v2 gnomad_v4
BS2 Met Met, supporting: gnomAD reports 372 homozygotes, including 342 exome homozygotes, challenging a fully penetrant dominant RET disorder.
gnomad_v2 gnomad_v4
BS3 Met Met at supporting strength: RET R982C alone showed no alteration of GDNF-dependent MAPK activity in the HEK293 assay, unlike the paired G691S/R982C construct.
PMID:22729463 PMID:21655256
BS4 Not assessed Not assessed: no adequately phenotyped unaffected familial carriers are documented to demonstrate non-segregation of RET c.2944C>T.
PMID:14633923 PMID:15741265 PMID:21655256
BP1 Not met Not met: RET disease mechanisms include established missense effects, so disease is not predominantly caused by truncating variants.
PMID:22837065 PMID:7647787
BP2 Met Met, supporting: p.R982C was on the paternal haplotype and pathogenic p.C634Y was maternal, demonstrating the variants in trans in the reported daughter.
PMID:21655256
BP3 N/A BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_020975.6:c.2944C>T in RET is a missense substitution predicted to produce NP_066124.1:p.(Arg982Cys). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Met Met at supporting strength: REVEL 0.282 is below the <=0.29 BP4 supporting threshold from the ClinGen SVI calibration.
revel
BP5 Met Met, supporting: affected individuals carried R982C with alternate RET variants, including established p.C634Y or G691S, providing an alternate molecular basis for disease.
PMID:21655256 PMID:22729463
BP6 Not met Not met: ClinVar has zero expert-panel submissions for exact R982C, so ordinary benign laboratory assertions cannot trigger BP6.
clinvar
BP7 N/A BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_020975.6:c.2944C>T in RET is a missense substitution predicted to produce NP_066124.1:p.(Arg982Cys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
generic_acmg_combination_rules
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