NM_020975.5:c.2895G>T

RET · NP_066124.1:p.(Lys965Asn) · NM_020975.5

GRCh37: chr10:43619212 G>T · GRCh38: chr10:43123764 G>T

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.(Lys965Asn)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and Canada (AF 0), below the <0.1% threshold.

BP4 (Supporting): SpliceAI max delta 0.00 and BayesDel −0.186 predict no impact on the gene product.

VUS: PM2 + BP4 (one supporting each) satisfies no Pathogenic, Likely Pathogenic, Benign, or Likely Benign rule in the generic ACMG/AMP 2015 combination table.

Final determination: Generic ACMG/AMP 2015 fallback combination rule: with only 1 pathogenic supporting (PM2) and 1 benign supporting (BP4) criterion applied, no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold is met, so the variant is classified as Variant of 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: missense substitution, not a null variant class, so no nonsense-mediated decay or truncation mechanism is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic variant produces the same p.Lys965Asn change; the only ClinVar entry is a 1-star VUS.	clinvar pm5_candidates PMID:25394175
PS2	Not assessed	Not assessed: no de novo occurrence or parental testing for this variant is recorded in any source.	clinvar PMID:25394175 generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional studies exist; OncoKB reports no variant-specific evidence and COSMIC lacks the variant.
PS4	Not assessed	Not assessed: no case-control or case-series data exist for this variant in any retrieved source.	clinvar
PM1	Not met	Not met: residue 965 shows no statistically significant cancer hotspot and no curated critical-domain annotation.	gnomad_v2 gnomad_v4
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and Canada (AF 0), below the <0.1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: RET cancer syndromes are autosomal dominant, so the recessive in-trans requirement does not apply.	clinvar generic_acmg_combination_rules
PM4	N/A	Not applicable: missense substitution with no protein length change, so there is nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no pathogenic alternate missense at residue 965; the screen found zero same-residue candidates.	pm5_candidates clinvar PMID:25394175
PM6	Not assessed	Not assessed: no de novo occurrence or parental genotypes are reported for this variant.	clinvar PMID:25394175 generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no co-segregation data — no affected relatives, pedigree, or segregation counts available.	clinvar PMID:25394175 generic_acmg_combination_rules
PP2	Not assessed	Not assessed: missense is a known RET disease mechanism, but no gene-level benign-missense-rate data was available.	oncokb
PP3	Not met	Not met: no in silico tool predicts damage — SpliceAI 0.00, BayesDel −0.186, REVEL 0.529 intermediate.	spliceai revel bayesdel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history information was available for this variant.	clinvar
PP5	Not met	Not met: no ClinVar expert-panel pathogenic assertion; the sole submission is a non-expert 1-star VUS.	clinvar
BA1	Not met	Not met: absent from gnomAD (AF 0), far below the >1% general-population threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: allele frequency 0 does not exceed the expected frequency for this rare dominant disorder.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: no observations in healthy controls — variant absent from gnomAD with no homozygous carriers.	gnomad_v2 gnomad_v4 gnomad_canada clinvar
BS3	Not assessed	Not assessed: no functional studies demonstrating a lack of damaging effect exist for this variant.
BS4	Not assessed	Not assessed: no family segregation data — no affected relatives tested or pedigree provided.	clinvar PMID:25394175 generic_acmg_combination_rules
BP1	Not met	Not met: activating missense variants are an established RET disease mechanism, so missense cannot be assumed benign.	oncokb pvs1_gene_context
BP2	Not assessed	Not assessed: no in-trans or in-cis observation with a pathogenic variant is documented for this variant.	clinvar generic_acmg_combination_rules
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): SpliceAI max delta 0.00 and BayesDel −0.186 both predict no impact (REVEL 0.529 indeterminate).	spliceai bayesdel revel pvs1_variant_assessment generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no reported case of this variant with an alternate molecular basis for disease.	clinvar
BP6	Not met	Not met: no ClinVar expert-panel benign assertion; the sole submission is a non-expert 1-star VUS.	clinvar
BP7	N/A	Not applicable: missense substitution, not a synonymous variant, so the silent-variant premise fails.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.