Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS1
The NM_020975.6(RET):c.3138C>A(p.Ala1046Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1046A) has been classified as Likely benign.
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]
RET Gene-Disease associations (from GenCC):
familial medullary thyroid carcinoma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
multiple endocrine neoplasia type 2A
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
Our verdict: Benign. The variant received -15 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.29).
BP6
Variant 10-43126673-C-A is Benign according to our data. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=2.82 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000233 (34/1461844) while in subpopulation AMR AF = 0.000335 (15/44724). AF 95% confidence interval is 0.000206. There are 0 homozygotes in GnomAdExome4. There are 18 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
All of Us Research Program, National Institutes of Health
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Hereditary cancer-predisposing syndromeBenign:2
Dec 29, 2014
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method: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. -
May 18, 2021
Sema4, Sema4
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:curation
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not providedBenign:1
Apr 26, 2018
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
RET-related disorderBenign:1
Oct 10, 2019
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing
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). -