Variant classification summary

NM_020975.6:c.2073T>C

RET · NP_066124.1:p.(Gly691=) · NM_020975.6

GRCh37: chr10:43610121 T>C · GRCh38: chr10:43114673 T>C

Gene: RET Transcript: NM_020975.6

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

RET

Transcript

NM_020975.6

Protein

NP_066124.1:p.(Gly691=)

gnomAD AF

1.8609798431069926e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): extremely rare in population databases, with gnomAD v4.1 allele frequency 1.86e-6 and no observed homozygotes.

2

BP7 (Supporting): SpliceAI max delta 0.002 across all splice categories indicates no significant splicing impact for this synonymous variant.

3

Overall: VUS under the generic ACMG/AMP 2015 combination rules (PMID:25741868), based solely on PM2 and BP7 at supporting strength.

Final determination: 1 PM supporting + 1 BP supporting does not meet any Pathogenic/LP/Benign/LB threshold under generic ACMG/AMP 2015, so the call defaults to VUS.

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 synonymous change (p.(Gly691=)) cannot trigger a null-variant mechanism such as nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: the synonymous change produces no altered amino acid to compare against a previously pathogenic change at this residue.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo occurrence with confirmed parental genotypes was documented.
PS3	Not assessed	Not assessed: no functional or experimental assay data for this variant were available.
PS4	Not assessed	Not assessed: no case-control, cohort, or affected-case series data for this variant were available.	generic_acmg_combination_rules
PM1	N/A	Not applicable: no altered residue exists to evaluate for a mutational hotspot, because the variant is synonymous (p.(Gly691=)).	generic_acmg_combination_rules
PM2	Met	Met (supporting): extremely rare in population databases, with gnomAD v4.1 allele frequency 1.86e-6 and no observed homozygotes.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Not applicable: RET disease here is autosomal dominant, so the recessive in-trans requirement cannot apply.	generic_acmg_combination_rules clinvar PMID:11739416
PM4	N/A	Not applicable: the synonymous change causes no change in protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a different pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental genotypes or family history support an assumed de novo occurrence.
PP1	Not assessed	Not assessed: no segregation or pedigree data were provided.
PP2	N/A	Not applicable: the gene's missense-constraint properties are irrelevant because the variant is synonymous.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.002 is far below the >=0.2 threshold for a splice-altering effect.	spliceai
PP4	Not assessed	Not assessed: no proband or family phenotype data were available to evaluate phenotype specificity.	generic_acmg_combination_rules
PP5	Not assessed	Not assessed: no ClinVar expert-panel pathogenic assertion for this exact variant is available.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 1.86e-6 is far below the >1% benign population-frequency threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: highest subpopulation allele frequency 1.63e-4 is far below the >0.3% benign-supporting threshold.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no unaffected adult homozygotes or phenotype-ascertained healthy cohort are documented.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no functional assay demonstrating normal function for this variant was available.
BS4	Not assessed	Not assessed: no segregation or non-segregation observations in family members were provided.
BP1	N/A	Not applicable: the gene's truncating-variant mechanism is irrelevant for this synonymous change.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no genotype, phase, or co-occurrence data could establish cis/trans configuration.	generic_acmg_combination_rules clinvar gnomad_v2 gnomad_v4
BP3	N/A	Not applicable: the variant does not alter protein length within a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: as a synonymous variant it has no missense prediction, and its splice evidence is assessed under BP7.
BP5	Not assessed	Not assessed: no alternative molecular diagnosis fully explaining an affected phenotype was documented.	generic_acmg_combination_rules
BP6	Not assessed	Not assessed: no ClinVar expert-panel benign assertion for this exact variant is available.	clinvar
BP7	Met	Met (supporting): SpliceAI max delta 0.002 across all splice categories indicates no significant splicing impact.	spliceai

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.