Variant: NM_177438.3(DICER1):c.832C>T (p.Leu278Phe)

CA7331564

254354 (ClinVar)

Gene: DICER1

Condition: DICER1-related tumor predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 9ed7a73b-8cef-456d-92b6-e7a94cffdd03

Approved on: 2025-02-25

Published on: 2025-06-04

HGVS expressions

NM_177438.3:c.832C>T
NM_177438.3(DICER1):c.832C>T (p.Leu278Phe)
NC_000014.9:g.95126651G>A
CM000676.2:g.95126651G>A
NC_000014.8:g.95592988G>A
CM000676.1:g.95592988G>A
NC_000014.7:g.94662741G>A
NG_016311.1:g.35772C>T
ENST00000529720.2:c.832C>T
ENST00000531162.7:c.832C>T
ENST00000674628.2:c.832C>T
ENST00000675540.2:c.832C>T
ENST00000696733.1:c.832C>T
ENST00000696734.1:c.832C>T
ENST00000696736.1:c.832C>T
ENST00000696737.1:c.832C>T
ENST00000696921.1:n.1938C>T
ENST00000696922.1:n.1241C>T
ENST00000696923.1:c.832C>T
ENST00000696924.1:c.832C>T
ENST00000696925.1:n.1241C>T
ENST00000696927.1:n.435C>T
ENST00000696928.1:n.1029C>T
ENST00000343455.8:c.832C>T
ENST00000393063.6:c.832C>T
ENST00000526495.6:c.832C>T
ENST00000532939.3:c.832C>T
ENST00000556045.6:c.832C>T
ENST00000674628.1:c.832C>T
ENST00000675995.1:c.832C>T
ENST00000343455.7:c.832C>T
ENST00000393063.5:c.832C>T
ENST00000526495.5:c.832C>T
ENST00000527414.5:c.832C>T
ENST00000541352.5:c.832C>T
NM_001195573.1:c.832C>T
NM_001271282.2:c.832C>T
NM_001291628.1:c.832C>T
NM_030621.4:c.832C>T
NM_177438.2:c.832C>T
NM_001271282.3:c.832C>T
NM_001291628.2:c.832C>T
NM_001395677.1:c.832C>T
NM_001395678.1:c.832C>T
NM_001395679.1:c.832C>T
NM_001395680.1:c.832C>T
NM_001395682.1:c.832C>T
NM_001395683.1:c.832C>T
NM_001395684.1:c.832C>T
NM_001395685.1:c.832C>T
NM_001395686.1:c.550C>T
NM_001395687.1:c.427C>T
NM_001395688.1:c.427C>T
NM_001395689.1:c.427C>T
NM_001395690.1:c.427C>T
NM_001395691.1:c.265C>T
NM_001395692.1:c.832C>T
NM_001395693.1:c.832C>T
NM_001395694.1:c.832C>T
NM_001395695.1:c.832C>T
NM_001395696.1:c.427C>T
NM_001395697.1:c.-737C>T
NM_001395698.1:c.427C>T
NM_001395699.1:c.832C>T
NM_001395700.1:c.832C>T
NR_172715.1:n.1046C>T
NR_172716.1:n.1177C>T
NR_172717.1:n.1344C>T
NR_172718.1:n.1344C>T
NR_172719.1:n.1177C>T
NR_172720.1:n.1177C>T

Uncertain Significance

• Met criteria codes: BP4 PS4_Supporting PP4 PS2

• Not Met criteria codes: BA1 BP2 BS3 BS4 BS1 BS2 PP1 PP3 PS3 PS1 PM1 PM5 PM2

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 1.3.0

Evidence submitted by expert panel

DICER1 and miRNA-Processing Gene VCEP

The NM_177438.3:c.832C>T variant in DICER1 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 278 (p.Leu278Phe). This variant received a total of 1 phenotype point in 1 proband, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 26925222). In the same individual, this variant was identified as a de novo occurrence with constitutional mosaicism (PS2; PMID: 26925222). This individual was also found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMID: 26925222). The total allele frequency in gnomAD v4.1.0 is 0.000003799 (6/1579166 alleles) with a highest population minor allele frequency of 0.00006640 (6/90360 alleles) in the South Asian population and with multiple alleles present in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.326); MaxEntScan and SpliceAI: no effect on splicing) (BP4). 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: PS4_Supporting, PS2, PP4, BP4. (Bayesian Points: 5; VCEP specifications version 1.3.0; 02/25/2025)

Met criteria codes

• BP4: In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.326); MaxEntScan and SpliceAI: no effect on splicing) (BP4).
• PS4_Supporting: This variant received a total of 1 phenotype point in 1 proband, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 26925222).
• PP4: At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMID: 26925222).
• PS2: This variant has been identified as a de novo occurrence with constitutional mosaicism in 1 individual (PS2; PMID: 26925222).

Not Met criteria codes

• BA1: 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
• BS3: 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
• 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
• 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
• 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
• 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: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: The total allele frequency in gnomAD v4.1.0 is 0.000003799 (6/1579166 alleles) with a highest population minor allele frequency of 0.00006640 (6/90360 alleles) in the South Asian population and with multiple alleles present in the South Asian population (PM2_Supporting, BS1, and BA1 are not met).