Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong
The NM_020975.6(RET):c.1264-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,613,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000064 ( 0 hom. )
Consequence
RET NM_020975.6 splice_region, splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.001751
2
Clinical Significance
Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
Variant 10-43111203-C-T is Benign according to our data. Variant chr10-43111203-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Likely benign, criteria provided, single submitter
clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Jul 31, 2024
- -
Multiple endocrine neoplasia type 2B Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Counsyl
Oct 31, 2016
- -
Multiple endocrine neoplasia type 2A Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Counsyl
Oct 31, 2016
- -
Multiple endocrine neoplasia, type 2 Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 24, 2024
- -
not provided Benign:1
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Sep 01, 2021
- -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Mar 02, 2023
This alteration is classified as 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. -
RET-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Oct 22, 2020
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -