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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_177438.3(DICER1):c.742T>A (p.Ser248Thr)

CA7331572

412066 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 6210ef36-be17-4358-ac4a-901c4b74363c
Approved on: 2024-08-27
Published on: 2024-09-16

HGVS expressions

NM_177438.3:c.742T>A
NM_177438.3(DICER1):c.742T>A (p.Ser248Thr)
NC_000014.9:g.95126741A>T
CM000676.2:g.95126741A>T
NC_000014.8:g.95593078A>T
CM000676.1:g.95593078A>T
NC_000014.7:g.94662831A>T
NG_016311.1:g.35682T>A
ENST00000529720.2:c.742T>A
ENST00000531162.7:c.742T>A
ENST00000674628.2:c.742T>A
ENST00000675540.2:c.742T>A
ENST00000696733.1:c.742T>A
ENST00000696734.1:c.742T>A
ENST00000696736.1:c.742T>A
ENST00000696737.1:c.742T>A
ENST00000696921.1:n.1848T>A
ENST00000696922.1:n.1151T>A
ENST00000696923.1:c.742T>A
ENST00000696924.1:c.742T>A
ENST00000696925.1:n.1151T>A
ENST00000696927.1:n.345T>A
ENST00000696928.1:n.939T>A
ENST00000343455.8:c.742T>A
ENST00000393063.6:c.742T>A
ENST00000526495.6:c.742T>A
ENST00000532939.3:c.742T>A
ENST00000556045.6:c.742T>A
ENST00000674628.1:c.742T>A
ENST00000675995.1:c.742T>A
ENST00000343455.7:c.742T>A
ENST00000393063.5:c.742T>A
ENST00000526495.5:c.742T>A
ENST00000527414.5:c.742T>A
ENST00000541352.5:c.742T>A
NM_001195573.1:c.742T>A
NM_001271282.2:c.742T>A
NM_001291628.1:c.742T>A
NM_030621.4:c.742T>A
NM_177438.2:c.742T>A
NM_001271282.3:c.742T>A
NM_001291628.2:c.742T>A
NM_001395677.1:c.742T>A
NM_001395678.1:c.742T>A
NM_001395679.1:c.742T>A
NM_001395680.1:c.742T>A
NM_001395682.1:c.742T>A
NM_001395683.1:c.742T>A
NM_001395684.1:c.742T>A
NM_001395685.1:c.742T>A
NM_001395686.1:c.460T>A
NM_001395687.1:c.337T>A
NM_001395688.1:c.337T>A
NM_001395689.1:c.337T>A
NM_001395690.1:c.337T>A
NM_001395691.1:c.175T>A
NM_001395692.1:c.742T>A
NM_001395693.1:c.742T>A
NM_001395694.1:c.742T>A
NM_001395695.1:c.742T>A
NM_001395696.1:c.337T>A
NM_001395697.1:c.-827T>A
NM_001395698.1:c.337T>A
NM_001395699.1:c.742T>A
NM_001395700.1:c.742T>A
NR_172715.1:n.956T>A
NR_172716.1:n.1087T>A
NR_172717.1:n.1254T>A
NR_172718.1:n.1254T>A
NR_172719.1:n.1087T>A
NR_172720.1:n.1087T>A
More

Likely Benign

Met criteria codes 2
BS2_Supporting BP4
Not Met criteria codes 15
PS2 PS4 PS3 PS1 PP4 PP1 PP3 PM1 PM5 BA1 PM2 BS4 BS3 BS1 BP2

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 1.3.0

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.742T>A variant in DICER1 is a missense variant predicted to cause substitution of serine by threonine at amino acid 248 (p.Ser248Thr). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The total allele frequency in gnomAD v4.0.0 is 0.000003433 (5/1456418 alleles) with a highest population minor allele frequency of 0.00001661 (1/60202 alleles) in a mixed population of unknown ancestry followed by 0.000003613 (4/1107216) in a European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.173; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 08/27/2024)
Met criteria codes
BS2_Supporting
This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). Invitae = 10 observations Ambry = 3 observations
BP4
In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.173; MaxEntScan and SpliceAI: no effect on splicing) (BP4).
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
0 points. 2 cases with personal (Invitae) or family history (Ambry) of ovarian cancer. 1 case with pituitary adenoma. 19 additional cases w/o DICER1 phenotypes.
PS3
None found
PS1
Same AA change not observed.
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 mutational hotspot or critical functional domain by the ClinGen DICER1 VCEP (PM1 not met).
PM5
Another missense variant 742T>G (p.Ser248Ala) in the same codon has been reported (ClinVar Variation ID: 2201523). However, this variant has not yet met the criteria to be classified as pathogenic by the ClinGen DICER1 VCEP (PM5 not met). Additionally, this variant has a greater (worse) Grantham score (99) than the variant under assessment (58) and, therefore, would not qualify for PM5 application, even if pathogenic.
BA1
The total allele frequency in gnomAD v4.0.0 is 0.000003433 (5/1456418 alleles) with a highest population minor allele frequency of 0.00001661 (1/60202 alleles) in a mixed population of unknown ancestry followed by 0.000003613 (4/1107216) in a European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
PM2
The total allele frequency in gnomAD v4.0.0 is 0.000003433 (5/1456418 alleles) with a highest population minor allele frequency of 0.00001661 (1/60202 alleles) in a mixed population of unknown ancestry followed by 0.000003613 (4/1107216) in a European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
None found
BS1
The total allele frequency in gnomAD v4.0.0 is 0.000003433 (5/1456418 alleles) with a highest population minor allele frequency of 0.00001661 (1/60202 alleles) in a mixed population of unknown ancestry followed by 0.000003613 (4/1107216) in a European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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