NM_020975.6:c.2776C>T

RET · NP_066124.1:p.(His926Tyr) · NM_020975.6

GRCh37: chr10:43617439 C>T · GRCh38: chr10:43121991 C>T

Gene: RET Transcript: NM_020975.6

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

RET

Transcript

NM_020975.6

Protein

NP_066124.1:p.(His926Tyr)

gnomAD AF

1.2396366377087548e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant is extremely rare in population databases, observed at an allele frequency of 0.00040% in gnomAD v2.1 (1/251,480 alleles, no homozygotes) and 0.00012% in gnomAD v4.1 (2/1,613,376 alleles, no homozygotes), meeting PM2 at supporting strength.

Multiple in silico tools predict no deleterious effect: BayesDel score 0.114 falls in the benign range, and SpliceAI delta score 0.02 predicts no splicing impact, meeting BP4 at supporting benign strength. REVEL score 0.571 is borderline and does not outweigh the other two lines of evidence.

This variant has been reported in ClinVar as Uncertain Significance by three clinical laboratories (ClinVar Variation ID: 578321). Three clinical laboratories independently classified it as VUS (SCV004028319, SCV002747231, SCV000830083). No expert panel review is available.

This variant has been observed in somatic cancers (COSMIC: COSV60689597, n=2) but lacks germline disease association evidence.

Overall classification: Uncertain Significance — one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) yield insufficient evidence to classify this variant as either pathogenic or benign. This is consistent with the ClinVar VUS classification.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, 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
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function; this is a missense substitution.
PM3	N/A	PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant; no phase data or recessive disease context applicable here.
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants; this is a missense substitution.
PVS1	N/A	This is a missense variant (p.His926Tyr), not a null variant (nonsense, frameshift, or canonical splice site). The variant does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No known pathogenic missense variant has been established at the same amino acid residue (His926). PM5 candidate search found zero same-residue pathogenic comparators.	pm5_candidates
PS2	Not met	No de novo observation confirmed for this variant. No publication or ClinVar submission reports a de novo event with confirmed maternity and paternity.	clinvar
PS3	Not met	No well-established functional studies supporting a damaging effect have been identified. OncoKB reports unknown oncogenic effect without variant-specific functional evidence. No publication describes functional characterization of p.His926Tyr.	oncokb
PS4	Not met	No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls. Three clinical laboratories report this variant as VUS in ClinVar, but no prevalence comparison data are available.	clinvar
PS5	Not met	No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain Significance from three clinical laboratories.	clinvar
PM1	Not met	Residue His926 is located within the tyrosine kinase domain of RET but is not in a statistically significant mutational hotspot. Hotspot analysis did not identify this residue as significantly enriched for pathogenic variation.
PM2	Met	This variant is extremely rare in population databases: allele frequency 0.00040% in gnomAD v2.1 (1/251,480 alleles, no homozygotes) and 0.00012% in gnomAD v4.1 (2/1,613,376 alleles, no homozygotes), well below the 0.1% PM2 threshold. Absent from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No established pathogenic missense variant at the same residue (His926) was identified. PM5 candidate search returned zero same-residue pathogenic comparators.	pm5_candidates
PM6	Not met	No assumed de novo observation without confirmation of paternity and maternity has been reported for this variant.	clinvar
PP1	Not met	No co-segregation data are available for this variant. No family studies have been reported.
PP2	Not assessed	Insufficient data to determine the rate of benign missense variation in RET specifically. RET has dual disease mechanisms: gain-of-function missense (MEN2) and loss-of-function (Hirschsprung disease). Missense constraint metrics (e.g., Z-score) are not explicitly available in the evidence brief.
PP3	Not met	In silico predictions are conflicting and do not provide multiple lines of evidence supporting a deleterious effect. REVEL score 0.571 is borderline (just above 0.5 threshold), but BayesDel score 0.114 is clearly in the benign range, and SpliceAI delta score 0.02 predicts no splicing impact. These do not constitute multiple concordant lines of computational evidence for pathogenicity.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available for assessment. The ClinVar submissions do not include detailed clinical phenotype information.	clinvar
PP5	Not met	No reputable source has recently reported this variant as pathogenic. ClinVar classification is Uncertain Significance from three clinical laboratories. All reviewed publications are clinical guidelines or practice recommendations that do not mention this specific variant.	clinvar
BA1	Not met	The variant is extremely rare, not common. Allele frequency is 0.00040% in gnomAD v2.1 and 0.00012% in gnomAD v4.1, far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency (0.00040% in v2.1, 0.00012% in v4.1) is far below the 0.3% BS1 threshold for a dominant disorder. This variant is not too common for a disease-causing variant.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygotes have been observed in gnomAD v2.1 or v4.1, and no healthy adult homozygous or hemizygous observation has been reported.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no damaging effect have been identified. No publication provides functional characterization of p.His926Tyr.	oncokb
BS4	Not met	No segregation data are available to assess lack of co-segregation with disease.
BP1	N/A	RET disease mechanisms include both loss-of-function (Hirschsprung disease via truncating variants) and gain-of-function (MEN2/MTC via activating missense). The gene does not primarily cause disease through truncating variants. BP1 (missense in gene where truncating variants primarily cause disease) does not apply.	pvs1_gene_context
BP2	Not met	No phase data are available. The variant has not been observed in trans with a known pathogenic RET variant or in cis with a pathogenic variant in any inheritance pattern.
BP4	Met	Multiple lines of computational evidence suggest no deleterious impact. BayesDel score 0.114 is in the benign range (well below damaging threshold). SpliceAI delta score 0.02 predicts no splicing impact. REVEL score 0.571 is borderline but does not outweigh the other two lines of evidence.	revel bayesdel spliceai
BP5	Not met	No case has been reported where this variant is found in an individual with an alternate molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign. ClinVar classification is VUS, not benign or likely benign.	clinvar
BP7	N/A	This is a missense variant (c.2776C>T, p.His926Tyr), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact.

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.