Classification rationale

PM2 VUS

RET c.1783G>A missense

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).

PM2 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_020975.6 · variants mapped to exon structure

RET NM_020975.6

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 21 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

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_v2gnomad_v4gnomad_canada

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗clinvar ↗

Assessed · not applied · 12 not met · 9 not assessed

Pathogenic

PS2 Not assessed: no de novo occurrence, proband data, or parental testing was available for this variant.

PS3 Not met: no functional studies exist for p.Glu595Lys; OncoKB classifies E595K as 'Unknown Oncogenic Effect' with no variant-specific functional evidence.

PS4 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).

PM1 Not met: p.Glu595 is not in a mutational hotspot — absent from CancerHotspots.org, and the established MEN2 cysteine hotspots (C609-C634) exclude it.

PM5 Not assessed: no pathogenic alternate missense change at Glu595 (e.g., E595Q/E595A) has been reported for comparison.

PM6 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: no segregation data exist — no pedigree, affected-relative genotyping, or segregation report for this variant.

PP2 Not assessed: no missense constraint data (e.g., gnomAD missense Z-score) was available to confirm a low rate of benign RET missense variation.

PP3 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.

PP4 Not assessed: no case-level phenotype documentation exists; the ClinVar record-level conditions are asserted labels with no documented carrier phenotype.

PP5 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.

Benign

BA1 Not met: maximum allele frequency 0.00336% is more than 300-fold below the >5% BA1 stand-alone threshold.

BS1 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.

BS2 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.

BS3 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.

BS4 Not assessed: no family studies exist — no non-segregation observations (unaffected carriers or affected non-carriers) for this variant.

BP1 Not met: RET is not primarily a truncating-disease gene — germline missense gain-of-function variants are a primary MEN2/FMTC mechanism.

BP2 Not met: no cis- or trans-phase observation of this variant with a pathogenic variant was reported.

BP4 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.

BP5 Not assessed: no case-level data document an alternate molecular basis of disease in a carrier of this variant.

BP6 Not met: no ClinVar expert-panel benign classification exists for this exact variant (0 expert-panel submissions), so the BP6 trigger is absent.

N/A · 6 PVS1 · PS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.86311e-06; MAF= 0.00019%, 3/1610212 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.35852e-05; MAF= 0.00336%, 2/59550 alleles, homozygotes = 0); grpmax FAF= 5.57e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.1413e-06; MAF= 0.00041%, 1/241470 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.95701e-05; MAF= 0.00296%, 1/33818 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,610,212
0 hom · FAF 0.00056%

Admixed American 2 / 59,550	0.0034%
European (non-Finnish) 1 / 1,178,830	8.5e-05%

+ 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.00041% · 1 / 241,470
0 hom

Admixed American

1 / 33,818

0.003%

+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 966506)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.47. BayesDel score = 0.197098.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RET, a receptor tyrosine kinase, is altered by mutation in medullary thyroid cancers and by chromosomal rearrangement in lung cancers, papillary thyro

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV60693777, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

35534704 ↗ The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR

26389271 ↗ Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®): Health Professional CLINVAR

34012068 ↗ ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR

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