Submissions for variant NM_177438.3(DICER1):c.5276A>G (p.Lys1759Arg)

gnomAD frequency: 0.00006  dbSNP: rs144259142

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	RCV000225800	SCV002540805	likely benign	DICER1-related tumor predisposition	2022-05-18	reviewed by expert panel	curation	The NM_177438.2:c.5276A>G variant in DICER1 is a missense variant predicted to cause substitution of Lysine by Arginine at amino acid 1759 (p.Lys1759Arg). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001071 in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors: 61756, 500031). The computational predictor REVEL gives a score of 0.444, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). This variant resides within the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PMID: 31342592)(PM1_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: (BS2, BP4, PM1_Supporting). (Bayesian Points: -4; VCEP specifications version 1; 02/11/2022).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225800	SCV000291710	likely benign	DICER1-related tumor predisposition	2025-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563154	SCV000661890	uncertain significance	Hereditary cancer-predisposing syndrome	2025-02-03	criteria provided, single submitter	clinical testing	The p.K1759R variant (also known as c.5276A>G), located in coding exon 23 of the DICER1 gene, results from an A to G substitution at nucleotide position 5276. The lysine at codon 1759 is replaced by arginine, an amino acid with highly similar properties. This alteration was observed in a cohort of 45 Lebanese patients with a reported family history of breast cancer (Jalkh N et al. BMC Med. Genomics. 2017 02;10:8). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001356404	SCV004221862	likely benign	not provided	2022-10-20	criteria provided, single submitter	clinical testing
Hereditary Cancer Group, L’Institut d'Investigació Biomèdica de Bellvitge	RCV000563154	SCV005442501	likely benign	Hereditary cancer-predisposing syndrome	2024-12-19	criteria provided, single submitter	clinical testing	BS2, PM1_supporting, BP4
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120643	SCV005872876	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
ITMI	RCV000120643	SCV000084804	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356404	SCV001551564	uncertain significance	not provided		no assertion criteria provided	clinical testing	The DICER1 p.K1759R variant was reported in an individual with breast cancer (Jalkh_2017_PMID: 28202063). The variant was identified in dbSNP (ID: rs144259142) and ClinVar (classified as uncertain significance by Ambry Genetics and as likely benign by Invitae), but was not identified in COSMIC. The variant was identified in control databases in 14 of 251452 chromosomes at a frequency of 0.00005568, and was observed at the highest frequency in the European (non-Finnish) population in 11 of 113732 chromosomes (freq: 0.00009672) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.K1759 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.