Variant classification summary

NM_020975.6:c.2753T>C

RET · NP_066124.1:p.(Met918Thr) · NM_020975.6

GRCh37: chr10:43617416 T>C · GRCh38: chr10:43121968 T>C

Gene: RET Transcript: NM_020975.6

Final call

VUS

PS3 strong PM1 moderate PM2 supporting PM6 moderate PP3 moderate

Variant details

Gene

RET

Transcript

NM_020975.6

Protein

NP_066124.1:p.(Met918Thr)

gnomAD AF

3.976490985294937e-06 (v2.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: PS3 strong shows damaging transformation and signaling effects for exact p.Met918Thr.

2

Pathogenic evidence: PM1 moderate places p.Met918Thr in the RET kinase substrate-binding pocket.

3

Pathogenic evidence: PM2 supporting shows an extremely low gnomAD frequency of 3.98e-06.

4

Pathogenic evidence: PM6 moderate records assumed de novo origin without confirmed maternity and paternity.

5

Pathogenic evidence: PP3 moderate is supported by REVEL 0.91.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong, two moderate, and one supporting pathogenic criterion does not match a listed pathogenic or likely pathogenic rule, and no benign rule is satisfied; therefore the call is 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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: p.Met918Thr is established pathogenic, but no different nucleotide change producing the same amino-acid substitution was established.	PMID:22584710 PMID:7824936
PS2	Not assessed	Not assessed: de novo origin is reported, but confirmed maternity and paternity are not documented for an affected individual.	clinvar
PS3	Met	Met at strong strength: exact p.Met918Thr caused RET transformation in independent cellular assays, including 98.5 ± 9.2 focus-forming units/µg DNA and increased soft-agar growth.	PMID:10679286 PMID:21810974 PMID:8755580
PS4	Not assessed	Not assessed: 34 affected carriers versus 0 of 93 controls is suggestive, but the total affected cohort is unavailable, preventing calculation of the required OR and 95% CI.	gnomad_v2 gnomad_v4
PM1	Met	Met: residue 918 lies in the RET kinase substrate-binding pocket, a critical functional region, with only 1/251,478 gnomAD v2.1 alleles and absence in v4.1.	PMID:22584710 gnomad_v2 gnomad_v4
PM2	Met	Met at supporting: gnomAD AF is 3.98e-06 (1/251478), below the PM2 supporting threshold of 0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: RET-associated MEN2B is dominantly inherited, so the recessive-disorder PM3 path does not apply.	PMID:7824936
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: M918V was studied at residue 918, but the available report calls it low or non-transforming rather than establishing pathogenicity.	PMID:21810974
PM6	Met	Met at moderate strength: two exact-variant ClinVar submissions report de novo origin without documented confirmation of maternity and paternity.	clinvar
PP1	Not assessed	Not assessed: no pedigree or informative meioses document cosegregation among multiple affected family members.	clinvar
PP2	Not assessed	Not assessed: RET missense activation is established, but no gene-level metric demonstrates a low rate of benign missense variation.	PMID:22584710 PMID:7824936
PP3	Met	Met at moderate strength: REVEL 0.91 meets the generic PP3 moderate threshold of >=0.773 for this missense variant.	revel
PP4	Not assessed	Not assessed: the materials link RET p.Met918Thr to MEN2B but do not provide this patient's specific phenotype or family history for PP4 evaluation.
PP5	Not met	Not met: ClinVar has Pathogenic/Likely pathogenic submissions, but zero expert-panel submissions means no qualifying exact-variant reputable-source assertion is available.	clinvar
BA1	Not met	Not met: gnomAD maximum observed AF is 8.79e-06, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: maximum observed AF is 8.79e-06, far below the generic BS1 default of 0.01 for this early-onset dominant syndrome.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD shows 0 homozygotes and provides no identified healthy adult observation carrying this variant.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: exact p.Met918Thr increased RET transformation, with 98.5 ± 9.2 focus-forming units/µg DNA, rather than showing preserved function.	PMID:10679286 PMID:21810974 PMID:8755580
BS4	Not assessed	Not assessed: no affected relatives without the variant are documented, so familial non-segregation cannot be evaluated.
BP1	Not met	Not met: RET disease is established through activating missense mutations such as M918T, not primarily through truncating variants.	PMID:22584710 PMID:7824936
BP2	Not assessed	Not assessed: no documented pathogenic allele in cis or trans with RET p.Met918Thr and no phase-tested affected-proband observation is available.	PMID:7824936
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.91 is above the generic BP4 supporting threshold of <=0.29 for this missense variant.	revel
BP5	Not assessed	Not assessed: no case evidence identifies an alternate molecular basis for disease alongside the RET p.Met918Thr variant.
BP6	Not met	Not met: no exact-variant reputable benign or likely benign expert-panel assertion is present; ClinVar submissions are Pathogenic or Likely pathogenic.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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