LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-31
Case ID: NM_020975.6_c.1900T_C_20261031_121551
Framework: ACMG/AMP 2015
Variant classification summary

NM_020975.6:c.1900T>C

RET  · NP_066124.1:p.(Cys634Arg)  · NM_020975.6
GRCh37: chr10:43609948 T>C  ·  GRCh38: chr10:43114500 T>C
Gene: RET Transcript: NM_020975.6
Final call
Pathogenic
PM1 moderate PM2 supporting PM6 moderate PP3 strong PP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
RET
Transcript
NM_020975.6
Protein
NP_066124.1:p.(Cys634Arg)
gnomAD AF
2.4881780440681215e-06 (v4.1)
ClinVar
Pathogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PM1 moderate is supported by a statistically significant RET C634 hotspot.
2
Pathogenic: PM2 supporting is supported by an extremely low gnomAD v4.1 allele frequency and zero homozygotes.
3
Pathogenic: PM6 moderate is supported by the variant's absence from both parents and multiple relatives in two MEN2A reports.
4
Pathogenic: PP3 strong is supported by REVEL 0.972 exceeding the generic 0.932 threshold.
5
Pathogenic: PP4 supporting is supported by the specific MEN2A phenotype with medullary thyroid carcinoma and pheochromocytoma.
Final determination: Under generic ACMG/AMP 2015 fallback rules, 1 strong criterion plus 2 moderate and 2 supporting pathogenic criteria yields Pathogenic.
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: the established pathogenic p.Cys634Arg evidence is the same c.1900T>C nucleotide change, with no qualifying alternate nucleotide change documented.
PMID:25741868 PMID:10522989 clinvar
PS2 Not met Not met: parental testing was negative, but only paternity was addressed and maternity confirmation required for PS2 was not documented.
PMID:10522989 PMID:11987030
PS3 Not assessed Not assessed: C634R was used only as a positive control in two assays, without variant-specific quantitative comparison to wild type or a validated diagnostic assay.
PMID:32293499 PMID:21690267
PS4 Not assessed Not assessed: qualifying case-control counts or an OR with 95% CI are unavailable, so the PS4 requirement OR >5.0 with CI excluding 1.0 cannot be tested.
PMID:10522989 PMID:11987030 gnomad_v4
PM1 Met Met: Cancer Hotspots identifies RET C634 as a statistically significant hotspot, although the partially parsed result requires screenshot confirmation.
PMID:25741868 hotspots
PM2 Met Met at supporting: gnomAD v4.1 grpmax FAF is 5.53e-06, below the PM2 threshold of 0.0001, with zero homozygotes.
gnomad_v4 gnomad_v2 PMID:25741868
PM3 N/A Not applicable: PM3 requires a recessive disorder and a pathogenic variant in trans, whereas this case concerns RET-associated dominant MEN2A.
PMID:10522989
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: codon 634 is recurrently disease-associated, but no specific different pathogenic missense substitution at residue 634 is documented.
PMID:25741868 pm5_candidates PMID:9230192
PM6 Met Met: RET C634R was absent from both parents and multiple relatives in two MEN2A reports, with maternity confirmation not documented.
PMID:10522989 PMID:11987030
PP1 Not assessed Not assessed: no multiple affected family members carrying RET C634R were reported, and the index case had no children for segregation analysis.
PMID:10522989 PMID:11987030
PP2 Not assessed Not assessed: RET activating missense disease mechanism is supported, but no gene-level benign-missense-rate metric is supplied.
PMID:25741868 oncokb PMID:21690267 PMID:32293499 gnomad_v4
PP3 Met Met, strong: REVEL 0.972 exceeds the generic PP3 threshold of 0.932 for missense variants.
revel
PP4 Met Met: MEN2A with medullary thyroid carcinoma and pheochromocytoma is a highly specific RET-associated phenotype meeting the PP4 supporting definition.
PMID:10522989 PMID:11987030
PP5 Not met Not met: ClinVar has zero exact-variant expert-panel submissions, so ordinary laboratory and aggregate Pathogenic labels cannot trigger PP5.
clinvar PMID:10522989
BA1 Not met Not met: gnomAD v4.1 grpmax FAF is 5.53e-06, far below the generic BA1 threshold of 0.05.
gnomad_v4 gnomad_v2 PMID:25741868
BS1 Not met Not met: gnomAD v4.1 grpmax FAF is 5.53e-06, below the generic BS1 threshold of 0.01.
gnomad_v4 gnomad_v2
BS2 Not assessed Not assessed: gnomAD reports carriers but does not document healthy-adult status or adequate early-onset follow-up.
gnomad_v4 gnomad_v2
BS3 Not assessed Not assessed: no study in the reviewed evidence demonstrates that C634R has no damaging effect on RET protein function or splicing.
BS4 Not assessed Not assessed: tested relatives were unaffected and negative, whereas BS4 requires an affected family member who lacks the variant.
PMID:10522989 PMID:11987030
BP1 Not met Not met: RET p.Cys634Arg has gain-of-function and oncogenic functional evidence, not a primarily truncating disease mechanism.
PMID:25741868 oncokb PMID:21690267 PMID:32293499
BP2 Not assessed Not assessed: p.Cys634Arg was reported in cis with Ala640Gly, but Ala640Gly lacks evidence here establishing it as pathogenic.
PMID:10522989
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 0.972 is above the generic BP4 supporting threshold of 0.29 for missense variants.
revel
BP5 Not assessed Not assessed: no case establishes an unrelated alternate molecular diagnosis explaining the phenotype; the reported second mutation is another RET variant on the same allele.
PMID:10522989
BP6 Not met Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present; the available record is non-expert Pathogenic/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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