Variant: NM_177438.3(DICER1):c.4313A>G (p.Tyr1438Cys)

Version: 1.1
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CA390869397

939082 (ClinVar)

Gene: DICER1 (HGNC:23405)

Condition: DICER1-related tumor predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: d99efc02-b33a-43ca-ab46-adbf89b1bb85

Approved on: 2026-02-24

Published on: 2026-03-23

HGVS expressions

NM_177438.3:c.4313A>G
NM_177438.3(DICER1):c.4313A>G (p.Tyr1438Cys)
NC_000014.9:g.95096607T>C
CM000676.2:g.95096607T>C
NC_000014.8:g.95562944T>C
CM000676.1:g.95562944T>C
NC_000014.7:g.94632697T>C
NG_016311.1:g.65816A>G
ENST00000529720.2:c.4313A>G
ENST00000531162.7:c.4313A>G
ENST00000674628.2:c.4313A>G
ENST00000675540.2:c.*963A>G
ENST00000696733.1:c.4313A>G
ENST00000696734.1:c.4313A>G
ENST00000696735.1:n.1300A>G
ENST00000696736.1:c.4313A>G
ENST00000696737.1:c.4313A>G
ENST00000696920.1:n.4576A>G
ENST00000696921.1:n.5419A>G
ENST00000696922.1:n.4722A>G
ENST00000696923.1:c.4313A>G
ENST00000696924.1:c.4313A>G
ENST00000696925.1:n.4722A>G
ENST00000343455.8:c.4313A>G
ENST00000393063.6:c.4313A>G
ENST00000526495.6:c.4313A>G
ENST00000532939.3:c.4313A>G
ENST00000556045.6:c.4313A>G
ENST00000675540.1:c.2058A>G
ENST00000675995.1:c.*2629A>G
ENST00000343455.7:c.4313A>G
ENST00000393063.5:c.4313A>G
ENST00000526495.5:c.4313A>G
ENST00000527414.5:c.4313A>G
ENST00000532939.2:c.348A>G
ENST00000541352.5:c.4313A>G
ENST00000556045.5:c.1007A>G
NM_001195573.1:c.4313A>G
NM_001271282.2:c.4313A>G
NM_001291628.1:c.4313A>G
NM_030621.4:c.4313A>G
NM_177438.2:c.4313A>G
NM_001271282.3:c.4313A>G
NM_001291628.2:c.4313A>G
NM_001395677.1:c.4313A>G
NM_001395678.1:c.4313A>G
NM_001395679.1:c.4313A>G
NM_001395680.1:c.4313A>G
NM_001395682.1:c.4313A>G
NM_001395683.1:c.4313A>G
NM_001395684.1:c.4313A>G
NM_001395685.1:c.4313A>G
NM_001395686.1:c.4031A>G
NM_001395687.1:c.3908A>G
NM_001395688.1:c.3908A>G
NM_001395689.1:c.3908A>G
NM_001395690.1:c.3908A>G
NM_001395691.1:c.3746A>G
NM_001395692.1:c.4313A>G
NM_001395693.1:c.4313A>G
NM_001395694.1:c.4313A>G
NM_001395695.1:c.4313A>G
NM_001395696.1:c.3908A>G
NM_001395697.1:c.2630A>G
NR_172715.1:n.4731A>G
NR_172716.1:n.4915A>G
NR_172717.1:n.4825A>G
NR_172718.1:n.4748A>G
NR_172719.1:n.4581A>G
NR_172720.1:n.4658A>G

Uncertain Significance

• Met criteria codes: PM2_Supporting BP4

• Not Met criteria codes: BA1 PP4 PP1 PP3 PM1 PM5 PM4 BS4 BS3 BS1 BS2 BP7 BP2 PVS1 PS4 PS2 PS3 PS1

Expert Panel

DICER1 and miRNA-Processing Gene VCEP

Criteria Specification Information

Criteria Specification: ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.4.0

Evidence submitted by expert panel

DICER1 and miRNA-Processing Gene VCEP

The NM_177438.3:c.4313A>G variant in DICER1 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 1438 (p.Tyr1438Cys). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.000001241 (2/1611784 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.2; MaxEntScan and SpliceAI: no effect on splicing) (BP4). 4 different missense variants, c.4313A>T (p.Tyr1438Phe), c.4313A>C (p.Tyr1438Ser), c.4312T>G (p.Tyr1438Asp), c.4312T>A (p.Tyr1438Asn), with Grantham scores equal to or less than the current variant have been reported in the same codon (ClinVar Variation ID: 2674813, 966537, 939902, 242107). However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.4.0; 02/24/2026)

Met criteria codes

• PM2_Supporting: This variant has an allele frequency of 0.000001241 (2/1611784 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
• BP4: In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.2; MaxEntScan and SpliceAI: no effect on splicing) (BP4).

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: This variant does not reside within a region of the RNAse IIIb domain that is defined as a critical functional domain by the ClinGen DICER1 VCEP (PM1 not met).
• PM5: 4 different missense variants, c.4313A>T (p.Tyr1438Phe), c.4313A>C (p.Tyr1438Ser), c.4312T>G (p.Tyr1438Asp), c.4312T>A (p.Tyr1438Asn), with Grantham scores equal to or less than the current variant have been reported in the same codon (ClinVar Variation ID: 2674813, 966537, 939902, 242107). However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met).
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: Axent-Saipovski Thesis, 2024, McGill University: Development of a miRNA-based reporter assay. Variant looked like WT. See Fig 12 (https://escholarship.mcgill.ca/concern/theses/mw22vc17n)
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors).
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline