Classification rationale

PM2 BP4 VUS

RET c.2486G>A missense · exon 14

PM2 (Supporting): extremely rare in population databases, 3/1,612,934 gnomAD v4.1 alleles (0.00019%) with 0 homozygotes, below the <0.1% threshold. BP4 (Supporting): REVEL 0.262 falls at or below the <=0.290 BP4_Supporting cutoff. VUS: one supporting pathogenic criterion (PM2) plus one supporting benign criterion (BP4) satisfies no ACMG/AMP 2015 Pathogenic or Benign combination rule.

PM2 + BP4 → VUS

Gene diagram · NM_020975.5 · variants mapped to exon structure

RET NM_020975.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 22 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 · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (Supporting): extremely rare, 3/1,612,934 alleles (0.00019%) in gnomAD v4.1 with 0 homozygotes, far below the <0.1% threshold.

gnomAD v2.1: 1/248,676 alleles, AF 4.0213e-06 (0.00040%), 0 homozygotes; highest Admixed American AF 2.89939e-05 (0.00290%).gnomAD v4.1: 3/1,612,934 alleles, AF 1.85996e-06 (0.00019%), 0 homozygotes; highest Admixed American AF 1.66594e-05 (0.00167%); grpmax FAF 2.8e-07.gnomAD-Canada v1.0: absent.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (Supporting): REVEL 0.262 falls at or below the <=0.290 BP4_Supporting cutoff.

REVEL score = 0.262 (source: local REVEL v1.3 predictor lookup), at/below the ClinGen SVI BP4_Supporting cutoff of <=0.290 for REVEL (Pejaver et al., PMID 36413997), consistent with a benign computational prediction at supporting strength.SpliceAI predicts no significant splice impact (max delta score = 0.011; DS_AG=0.011, DS_AL=0.003, DS_DG=0.0, DS_DL=0.0), consistent with no splice-based pathogenic signal counteracting the benign in-silico missense prediction.

spliceai ↗

Assessed · not applied · 6 not met · 16 not assessed

Pathogenic

PS1 Not assessed: insufficient evidence was available to compare this variant against an established pathogenic change at the same residue.

PS2 Not assessed: no proband-level parental genotypes or de novo confirmation for p.Ser829Asn were available.

PS3 Not assessed: no functional assay data (kinase activation, transformation, or cell-based) for p.Ser829Asn were available.

PS4 Not assessed: no case series or affected individuals carrying this exact variant were identified.

PM1 Not assessed: insufficient evidence was available to determine whether p.Ser829Asn lies in a mutational hotspot or critical domain.

PM3 Not assessed: no observation of this variant in trans with a known pathogenic RET variant was available.

PM5 Not assessed: insufficient evidence was available to compare p.Ser829Asn with a previously established pathogenic missense at the same codon.

PM6 Not assessed: no presumed de novo occurrence without confirmed parental testing was documented.

PP1 Not assessed: no affected relatives or family segregation data were available.

PP2 Not assessed: insufficient evidence was available to evaluate this variant in a gene with low rates of benign missense variation.

PP3 Not met: REVEL 0.262 is below the >=0.644 PP3_Supporting threshold.

PP4 Not assessed: no patient-specific phenotype or diagnostic findings for this variant carrier were available.

PP5 Not met: ClinVar classifies this variant as uncertain significance with no expert-panel submission.

Benign

BA1 Not met: highest population frequency 0.00290% is far below the >1% BA1 threshold.

BS1 Not met: highest subpopulation frequency 0.00290% is far below the >0.3% BS1 threshold.

BS2 Not met: no healthy-adult carriers documented, only rare heterozygous alleles with no phenotype data.

BS3 Not assessed: no functional assay data demonstrating normal protein function were available.

BS4 Not assessed: no family data showing failure of this variant to segregate with disease were available.

BP1 Not assessed: insufficient evidence was available to evaluate presence of a known benign variant in trans.

BP2 Not assessed: no second RET variant or cis/trans phase data were available.

BP5 Not assessed: no evidence that this variant occurred with a confirmed alternative molecular cause of disease.

BP6 Not met: no expert-panel benign classification; ClinVar record is uncertain significance from three laboratories.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.85996e-06; MAF= 0.00019%, 3/1612934 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66594e-05; MAF= 0.00167%, 1/60026 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.0213e-06; MAF= 0.00040%, 1/248676 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89939e-05; MAF= 0.00290%, 1/34490 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 / 1,612,934
0 hom · FAF 2.8e-05%

Admixed American 1 / 60,026	0.0017%
European (non-Finnish) 2 / 1,179,944	0.00017%

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

gnomAD v2.1

0.0004% · 1 / 248,676
0 hom

Admixed American

1 / 34,490

0.0029%

+ 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 (3 clinical laboratories). (ClinVarID = 1791991)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.262. BayesDel score = -0.304934.

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 not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers 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.

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

20301434 ↗ Multiple Endocrine Neoplasia Type 2. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

25810047 ↗ Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. CLINVAR

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

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