Variant classification summary

NM_020975.6:c.2711C>T

RET · NP_066124.1:p.(Ser904Phe) · NM_020975.6

GRCh37: chr10:43615632 C>T · GRCh38: chr10:43120184 C>T

Gene: RET Transcript: NM_020975.6

Final call

Likely Pathogenic

PS3 supporting PM1 moderate PM2 supporting PP1 moderate PP3 supporting PP4 supporting

Variant details

Gene

RET

Transcript

NM_020975.6

Protein

NP_066124.1:p.(Ser904Phe)

gnomAD AF

6.19902080267401e-07 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_020975.6:c.2711C>T (p.Ser904Phe) is a missense variant in exon 15 of the RET gene, located in the activation loop of the tyrosine kinase domain.

2

This variant is absent from gnomAD v2.1 and gnomAD-Canada, and is present in gnomAD v4.1 at an extremely low allele frequency of 6.2e-7 (1/1,613,158 alleles), meeting PM2_supporting.

3

The variant is located in the activation loop of the RET kinase domain (codon 904, between autophosphorylation residues Y900 and Y905), a critical functional domain and known mutational hotspot for MEN2-associated variants, meeting PM1_moderate.

4

In vitro functional studies demonstrate that S904F increases RET kinase ATP affinity, accelerates autophosphorylation, and confers gain-of-function transforming activity, consistent with the established pathogenic mechanism of RET in MEN2, meeting PS3_supporting.

5

The variant cosegregates with medullary thyroid carcinoma in multiple affected family members across at least two families; in the largest reported family, 7 of 10 carriers developed MTC across multiple generations, meeting PP1_moderate.

6

REVEL in silico prediction score of 0.821 supports a deleterious effect on protein function, meeting PP3_supporting.

7

The variant has been observed in multiple individuals with medullary thyroid carcinoma, a phenotype highly specific for RET-related hereditary cancer syndromes, meeting PP4_supporting.

8

Two moderate criteria (PM1, PP1) and four supporting criteria (PS3, PM2, PP3, PP4) are met. Per ACMG/AMP 2015 combination rules (PMID:25741868), this combination is consistent with a classification of Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	This missense variant (c.2711C>T, p.Ser904Phe) does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants; PVS1 is not applicable to missense substitutions.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence is available that a different nucleotide change at codon 904 producing the same amino acid substitution (p.Ser904Phe) has been established as pathogenic; PS1 cannot be applied without a known pathogenic comparator arising from an alternative nucleotide change at the same residue.
PS2	Not met	No de novo observation with confirmed paternity and maternity has been reported for this variant; the variant has been observed as inherited in multiple family members (PMID:33167350).	PMID:33167350
PS3	Met	In vitro functional studies demonstrate that the S904F substitution increases RET kinase ATP affinity, accelerates autophosphorylation, and confers gain-of-function transforming activity. These functional defects are consistent with the established gain-of-function mechanism of RET in MEN2 and medullary thyroid carcinoma.	PMID:29434222 PMID:21810974
PS4	Not met	The variant has been observed in affected families but there are insufficient case-control data to demonstrate a statistically significant increased prevalence in affected individuals compared to population controls. Only two families with MTC are reported, and the variant is not observed at sufficient scale in case-control cohorts.	PMID:33167350
PS5	Not met	ClinVar classification for this variant is split: Likely pathogenic (2 clinical laboratories) and Uncertain significance (1 clinical laboratory), with review status of 'criteria provided, single submitter' and no expert panel consensus. The available evidence has been independently reviewed; PS5/PP5 should not be applied when the underlying evidence is available for evaluation.	clinvar
PM1	Met	The variant is located in the activation loop of the RET tyrosine kinase domain (codon 904, situated between autophosphorylation residues Y900 and Y905), a critical and well-established functional domain. The RET kinase domain is a known mutational hotspot for pathogenic MEN2-associated variants, and no benign variation has been established at this residue within the activation loop.	PMID:29434222 PMID:33167350
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD-Canada and is present in gnomAD v4.1 at an extremely low allele frequency (1/1,613,158 alleles, AF = 6.2e-7), well below the PM2 threshold of 0.1%. No homozygotes have been observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue comparator missense variants with an established pathogenic classification were identified in ClinVar or the literature; classic PM5 semantics (different amino acid change at the same residue already established as pathogenic) cannot be applied.	pm5_candidates
PM6	Not met	No de novo observation (even without confirmed paternity/maternity) has been reported for this variant; the variant segregates as inherited in multiple families with MTC.	PMID:33167350
PP1	Met	The variant cosegregates with medullary thyroid carcinoma in multiple affected family members across at least two families. In the largest reported family (PMID:33167350), 7 of 10 carriers developed MTC across multiple generations (average age at diagnosis 46.3 years). A prior report describes a father and son both affected with adult-onset MTC. RET is a gene definitively known to cause MEN2/FMTC.	PMID:33167350
PP2	Not assessed	Insufficient gene-level missense constraint data (e.g., gnomAD Z-score, missense depletion metrics) were available to determine whether RET has a low rate of benign missense variation. HCI prior data was not available for this gene.
PP3	Met	REVEL score of 0.821 exceeds the 0.7 threshold for pathogenic prediction, supporting a deleterious effect on protein function. BayesDel score of 0.3192 provides borderline additional support. SpliceAI predicts no splicing impact (max delta = 0.0). Multiple in silico algorithms support a deleterious prediction.	revel bayesdel spliceai
PP4	Met	The variant has been observed in multiple individuals with medullary thyroid carcinoma, a phenotype that is highly specific for RET-related hereditary cancer syndromes (MEN2A, MEN2B, FMTC). MTC is a hallmark feature of RET-associated disease with high positive predictive value.	PMID:33167350 clinvar
PP5	Not met	ClinVar classification is split between Likely pathogenic (2 labs) and Uncertain significance (1 lab) with review status of 'criteria provided, single submitter.' No expert panel or multi-submitter consensus exists. The available evidence has been independently evaluated; PP5 should not be applied when the underlying evidence is available for direct assessment.	clinvar
BA1	Not met	The maximum population allele frequency in gnomAD (1.6e-5 in Remaining individuals) is far below the BA1 threshold of 1%.	gnomad_v4
BS1	Not met	The maximum population allele frequency in gnomAD (1.6e-5) is far below the BS1 threshold of 0.3%.	gnomad_v4
BS2	Not met	Only 1 allele observed in gnomAD v4.1 across 1.6 million alleles; insufficient observation in healthy adults to apply BS2, which requires observation in healthy adults for a disorder expected to have full penetrance at an early age.	gnomad_v4
BS3	Not met	Available functional studies demonstrate gain-of-function effects (increased ATP affinity, accelerated autophosphorylation, transforming activity) consistent with a pathogenic mechanism, not a benign effect. BS3 is not supported.	PMID:29434222 PMID:21810974
BS4	Not met	The variant does segregate with disease in reported families. In PMID:33167350, 7 of 10 carriers across multiple generations developed MTC, and a prior report describes a father-son pair both affected. This is inconsistent with BS4 (lack of segregation).	PMID:33167350
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. RET-associated MEN2 is caused by gain-of-function missense variants; truncating variants are not the primary disease mechanism. BP1 is therefore not applicable.
BP2	Not met	No evidence was identified that this variant has been observed in trans with a known pathogenic RET variant in a fully penetrant dominant disorder.
BP4	Not met	REVEL score of 0.821 supports a deleterious effect, contradicting BP4 which requires multiple lines of computational evidence suggesting no impact on gene product. BayesDel score of 0.3192 is borderline and does not overcome the strong REVEL prediction.	revel bayesdel spliceai
BP5	Not met	No evidence was identified that this variant has been found in a case with an alternate molecular basis for disease that would explain the phenotype independently.
BP6	Not met	No reputable source reports this variant as benign or likely benign. ClinVar classifications are Likely pathogenic (2 labs) or Uncertain significance (1 lab).	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. This variant is a missense substitution (c.2711C>T, p.Ser904Phe) and is therefore not eligible for BP7.

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