NM_177438.2(DICER1):c.1124C>G (p.Pro375Arg) AND DICER1-related pleuropulmonary blastoma cancer predisposition syndrome

Clinical significance:Benign/Likely benign (Last evaluated: Dec 2, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000231396.10

Allele description [Variation Report for NM_177438.2(DICER1):c.1124C>G (p.Pro375Arg)]

NM_177438.2(DICER1):c.1124C>G (p.Pro375Arg)

Gene:
DICER1:dicer 1, ribonuclease III [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q32.13
Genomic location:
Preferred name:
NM_177438.2(DICER1):c.1124C>G (p.Pro375Arg)
HGVS:
  • NC_000014.9:g.95124448G>C
  • NG_016311.1:g.37975C>G
  • NM_001195573.1:c.1124C>G
  • NM_001271282.3:c.1124C>G
  • NM_001291628.1:c.1124C>G
  • NM_030621.4:c.1124C>G
  • NM_177438.2:c.1124C>G
  • NP_001182502.1:p.Pro375Arg
  • NP_001258211.1:p.Pro375Arg
  • NP_001278557.1:p.Pro375Arg
  • NP_085124.2:p.Pro375Arg
  • NP_803187.1:p.Pro375Arg
  • LRG_492t1:c.1124C>G
  • LRG_492:g.37975C>G
  • LRG_492p1:p.Pro375Arg
  • NC_000014.8:g.95590785G>C
  • p.P375R
Protein change:
P375R
Links:
dbSNP: rs148758903
NCBI 1000 Genomes Browser:
rs148758903
Molecular consequence:
  • NM_001195573.1:c.1124C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001271282.3:c.1124C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001291628.1:c.1124C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_030621.4:c.1124C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_177438.2:c.1124C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
DICER1-related pleuropulmonary blastoma cancer predisposition syndrome (PPBFTDS)
Synonyms:
PPB FAMILIAL TUMOR AND DYSPLASIA SYNDROME; DICER1 syndrome
Identifiers:
MONDO: MONDO:0017288; MedGen: C3839822; OMIM: 601200

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000291603Invitaecriteria provided, single submitter
Likely benign
(Dec 2, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000389766Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Benign
(Jan 12, 2018)
germlineclinical testing

Citation Link,

SCV000891032St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospitalcriteria provided, single submitter
Likely benign
(Oct 7, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000291603.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000389766.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital, SCV000891032.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The DICER1 c.1124C>G (p.Pro375Arg) missense change has a maximum subpopulation frequency of 0.05% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/14-95590785-G-C). This population frequency is higher than expected for DICER1-related cancer predisposition syndrome (BS1, PMID: 24761742). Although this variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533), but in silico tools are not in agreement about the effect of this variant on protein function. This variant has been reported in an individual with papillary thyroid carcinoma whose tumor harbored a somatic DICER1 p.D1810Y variant and loss of the allele that carried the germline p.P375R variant (BP5; PMID: 29474644). This suggests that this variant is not deleterious. To our knowledge, this variant has not been reported in individuals with a personal or family history suggestive of DICER1 Tumor Predisposition syndrome (internal data and literature review). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP5, PP2.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 6, 2021

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