Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_177438.3(DICER1):c.3553G>A (p.Ala1185Thr)

CA158273

133970 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f9b0da96-b8bc-4ebc-9b7f-1bba9acb1e97
Approved on: 2023-08-22
Published on: 2023-09-01

HGVS expressions

NM_177438.3:c.3553G>A
NM_177438.3(DICER1):c.3553G>A (p.Ala1185Thr)
NC_000014.9:g.95103843C>T
CM000676.2:g.95103843C>T
NC_000014.8:g.95570180C>T
CM000676.1:g.95570180C>T
NC_000014.7:g.94639933C>T
NG_016311.1:g.58580G>A
ENST00000343455.8:c.3553G>A
ENST00000393063.6:c.3553G>A
ENST00000526495.6:c.3553G>A
ENST00000532939.3:c.3553G>A
ENST00000556045.6:c.3553G>A
ENST00000675540.1:c.1298G>A
ENST00000675995.1:c.*1869G>A
ENST00000343455.7:c.3553G>A
ENST00000393063.5:c.3553G>A
ENST00000526495.5:c.3553G>A
ENST00000527414.5:c.3553G>A
ENST00000541352.5:c.3553G>A
ENST00000554367.1:n.762G>A
ENST00000556045.5:c.247G>A
NM_001195573.1:c.3553G>A
NM_001271282.2:c.3553G>A
NM_001291628.1:c.3553G>A
NM_030621.4:c.3553G>A
NM_177438.2:c.3553G>A
NM_001271282.3:c.3553G>A
NM_001291628.2:c.3553G>A
NM_001395677.1:c.3553G>A
NM_001395678.1:c.3553G>A
NM_001395679.1:c.3553G>A
NM_001395680.1:c.3553G>A
NM_001395682.1:c.3553G>A
NM_001395683.1:c.3553G>A
NM_001395684.1:c.3553G>A
NM_001395685.1:c.3553G>A
NM_001395686.1:c.3271G>A
NM_001395687.1:c.3148G>A
NM_001395688.1:c.3148G>A
NM_001395689.1:c.3148G>A
NM_001395690.1:c.3148G>A
NM_001395691.1:c.2986G>A
NM_001395692.1:c.3553G>A
NM_001395693.1:c.3553G>A
NM_001395694.1:c.3553G>A
NM_001395695.1:c.3553G>A
NM_001395696.1:c.3148G>A
NM_001395697.1:c.1870G>A
NR_172715.1:n.3971G>A
NR_172716.1:n.4155G>A
NR_172717.1:n.4065G>A
NR_172718.1:n.3988G>A
NR_172719.1:n.3821G>A
NR_172720.1:n.3898G>A
More

Benign

Met criteria codes 3
BP4 BS1 BS2
Not Met criteria codes 23
BP5 BP7 BP2 BP3 BP1 PS1 PS4 PS3 PS2 PP4 PP1 PP3 PP2 PM5 PM3 PM1 PM4 PM6 PM2 PVS1 BA1 BS3 BS4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.2.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
DICER1 and miRNA-Processing Gene VCEP
The NM_177438.2:c.3553G>A variant in DICER1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 1185 (p.Ala1185Thr). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; ClinVar SCV: SCV000661803.4, SCV000291663.10; PMIDs: 24728327). The highest population minor allele frequency in gnomAD v3.1.2 is 0.002 (45/15,076 alleles) in Latino/Admixed American populations, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.048; MaxEntScan and SpliceAI: no effect on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS1, BS2, BP4. (Bayesian Points: -9; VCEP specifications version 1.2.0; 08/22/23)
Met criteria codes
BP4
In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.048; MaxEntScan and SpliceAI: no effect on splicing) (BP4).
BS1
The highest population minor allele frequency in gnomAD v3.1.2 is 0.002 (45/15,076 alleles) in Latino/Admixed American populations, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1).
BS2
This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; ClinVar SCV: SCV000661803.4, SCV000291663.10; PMIDs: 24728327)
Not Met criteria codes
BP5
This evidence code is not currently applicable for DICER1 VCEP curations.
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
BP3
This evidence code is not currently applicable for DICER1 VCEP curations.
BP1
This evidence code is not currently applicable for DICER1 VCEP curations.
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This variant received a total of 0 phenotype points in over 300 probands. (PS4 not met; GTR ID: 61756, 500031, 26957, 239772).
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
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
PP2
This evidence code is not currently applicable for DICER1 VCEP curations.
PM5
Another missense variant, c.3553G>C (p.Ala1185Pro), in the same codon has been reported (ClinVar Variation ID: 568319). However, this variant has not met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met).
PM3
This evidence code is not currently applicable for DICER1 VCEP curations.
PM1
This variant does not reside within a region of the RNAse IIIb domain that is defined as a mutational hotspot or critical functional domain by the ClinGen DICER1 VCEP (PM1 not met).
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
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
BA1
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
Curation History
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