Classification rationale

PM2 BP7 VUS

RET c.2073T>C synonymous · exon 11

PM2 (Supporting): extremely rare in population databases, with gnomAD v4.1 allele frequency 1.86e-6 and no observed homozygotes. BP7 (Supporting): SpliceAI max delta 0.002 across all splice categories indicates no significant splicing impact for this synonymous variant. Overall: VUS under the generic ACMG/AMP 2015 combination rules (PMID:25741868), based solely on PM2 and BP7 at supporting strength.

PM2 + BP7 → VUS

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

RET NM_020975.6

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 16 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 in population databases, with gnomAD v4.1 allele frequency 1.86e-6 and no observed homozygotes.

gnomAD v4.1 reports 3/1,612,054 alleles (AF 1.86098e-6; homozygotes 0), with group maximum FAF 2.8e-7.gnomAD v2.1 reports 1/250,230 alleles (AF 3.99632e-6; homozygotes 0).The variant is absent from gnomAD-Canada v1.0.

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

✓

BP7 supporting Benign

Met (supporting): SpliceAI max delta 0.002 across all splice categories indicates no significant splicing impact.

SpliceAI Lookup (source_registry key 'spliceai') for NM_020975.6:c.2073T>C: max_delta_score = 0.002 (DS_AG=0.002, DS_AL=0.001, DS_DG=0.002, DS_DL=0.0); prefetch evidence_sentence states 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).'Variant confirmed synonymous via normalization: NP_066124.1:p.(G691=).

spliceai ↗

Assessed · not applied · 3 not met · 13 not assessed

Pathogenic

PS2 Not assessed: no de novo occurrence with confirmed parental genotypes was documented.

PS3 Not assessed: no functional or experimental assay data for this variant were available.

PS4 Not assessed: no case-control, cohort, or affected-case series data for this variant were available.

PM6 Not assessed: no parental genotypes or family history support an assumed de novo occurrence.

PP1 Not assessed: no segregation or pedigree data were provided.

PP3 Not met: SpliceAI max delta 0.002 is far below the >=0.2 threshold for a splice-altering effect.

PP4 Not assessed: no proband or family phenotype data were available to evaluate phenotype specificity.

PP5 Not assessed: no ClinVar expert-panel pathogenic assertion for this exact variant is available.

Benign

BA1 Not met: gnomAD v4.1 allele frequency 1.86e-6 is far below the >1% benign population-frequency threshold.

BS1 Not met: highest subpopulation allele frequency 1.63e-4 is far below the >0.3% benign-supporting threshold.

BS2 Not assessed: no unaffected adult homozygotes or phenotype-ascertained healthy cohort are documented.

BS3 Not assessed: no functional assay demonstrating normal function for this variant was available.

BS4 Not assessed: no segregation or non-segregation observations in family members were provided.

BP2 Not assessed: no genotype, phase, or co-occurrence data could establish cis/trans configuration.

BP5 Not assessed: no alternative molecular diagnosis fully explaining an affected phenotype was documented.

BP6 Not assessed: no ClinVar expert-panel benign assertion for this exact variant is available.

N/A · 10 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP4

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.86098e-06; MAF= 0.00019%, 3/1612054 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60077e-05; MAF= 0.00160%, 1/62470 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.99632e-06; MAF= 0.00040%, 1/250230 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163292; MAF= 0.01633%, 1/6124 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 / 1,612,054
0 hom · FAF 2.8e-05%

Remaining individuals 1 / 62,470	0.0016%
European (non-Finnish) 2 / 1,179,802	0.00017%

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

gnomAD v2.1

0.0004% · 1 / 250,230
0 hom

Remaining individuals

1 / 6,124

0.016%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), 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 Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 1126022)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

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 ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

11739416 ↗ Guidelines for diagnosis and therapy of MEN type 1 and type 2. CLINVAR

8918855 ↗ The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. CLINVAR

20301434 ↗ Multiple Endocrine Neoplasia Type 2. CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR

27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR