Submissions for variant NM_177438.3(DICER1):c.1802T>C (p.Ile601Thr)

dbSNP: rs760966585

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	RCV000654420	SCV005686352	likely benign	DICER1-related tumor predisposition	2025-01-07	reviewed by expert panel	curation	The NM_177438.3:c.1802T>C variant in DICER1 is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 601 (p.Ile601Thr). 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 v4.1.0 is 0.000007434 (12/1,614,166 alleles) with a highest population minor allele frequency of 0.00001017 (12/1,179,996 alleles) in 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: 0.033; 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; 01/07/2025)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654420	SCV000776314	uncertain significance	DICER1-related tumor predisposition	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 601 of the DICER1 protein (p.Ile601Thr). This variant is present in population databases (rs760966585, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 543609). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DICER1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001013236	SCV001173794	likely benign	Hereditary cancer-predisposing syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001756106	SCV002005389	uncertain significance	not provided	2024-01-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge