Variant classification summary

NM_020975.5:c.2486G>A

RET · NP_066124.1:p.(Ser829Asn) · NM_020975.5

GRCh37: chr10:43615072 G>A · GRCh38: chr10:43119624 G>A

Gene: RET Transcript: NM_020975.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

RET

Transcript

NM_020975.5

Protein

NP_066124.1:p.(Ser829Asn)

gnomAD AF

1.8599645118771133e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

BP4 (Supporting): REVEL 0.262 falls at or below the <=0.290 BP4_Supporting cutoff.

3

VUS: one supporting pathogenic criterion (PM2) plus one supporting benign criterion (BP4) satisfies no ACMG/AMP 2015 Pathogenic or Benign combination rule.

Final determination: Generic ACMG/AMP 2015 fallback: 1 supporting pathogenic criterion (PM2) plus 1 supporting benign criterion (BP4) meets none of the defined Pathogenic/Likely Pathogenic/Benign/Likely Benign combinations, so the variant is Uncertain Significance.

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: this is a missense variant (p.Ser829Asn), so no null-variant mechanism such as nonsense-mediated decay applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: insufficient evidence was available to compare this variant against an established pathogenic change at the same residue.
PS2	Not assessed	Not assessed: no proband-level parental genotypes or de novo confirmation for p.Ser829Asn were available.
PS3	Not assessed	Not assessed: no functional assay data (kinase activation, transformation, or cell-based) for p.Ser829Asn were available.
PS4	Not assessed	Not assessed: no case series or affected individuals carrying this exact variant were identified.
PM1	Not assessed	Not assessed: insufficient evidence was available to determine whether p.Ser829Asn lies in a mutational hotspot or critical domain.
PM2	Met	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 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no observation of this variant in trans with a known pathogenic RET variant was available.	PMID:25741868
PM4	N/A	Not applicable: missense substitution, so no protein length change occurs.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: insufficient evidence was available to compare p.Ser829Asn with a previously established pathogenic missense at the same codon.
PM6	Not assessed	Not assessed: no presumed de novo occurrence without confirmed parental testing was documented.
PP1	Not assessed	Not assessed: no affected relatives or family segregation data were available.
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate this variant in a gene with low rates of benign missense variation.
PP3	Not met	Not met: REVEL 0.262 is below the >=0.644 PP3_Supporting threshold.	revel spliceai
PP4	Not assessed	Not assessed: no patient-specific phenotype or diagnostic findings for this variant carrier were available.	PMID:25810047
PP5	Not met	Not met: ClinVar classifies this variant as uncertain significance with no expert-panel submission.	clinvar
BA1	Not met	Not met: highest population frequency 0.00290% is far below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: highest subpopulation frequency 0.00290% is far below the >0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no healthy-adult carriers documented, only rare heterozygous alleles with no phenotype data.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal protein function were available.
BS4	Not assessed	Not assessed: no family data showing failure of this variant to segregate with disease were available.
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate presence of a known benign variant in trans.
BP2	Not assessed	Not assessed: no second RET variant or cis/trans phase data were available.	PMID:25741868
BP3	N/A	Not applicable: missense substitution, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): REVEL 0.262 falls at or below the <=0.290 BP4_Supporting cutoff.	revel spliceai
BP5	Not assessed	Not assessed: no evidence that this variant occurred with a confirmed alternative molecular cause of disease.
BP6	Not met	Not met: no expert-panel benign classification; ClinVar record is uncertain significance from three laboratories.	clinvar
BP7	N/A	Not applicable: missense substitution, not a synonymous variant.	generic_acmg_combination_rules

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