chr10-43114546-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_020975.6(RET):c.1946C>T(p.Ser649Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000445 in 1,610,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S649S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1946C>T | p.Ser649Leu | missense_variant | 11/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1946C>T | p.Ser649Leu | missense_variant | 11/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000381 AC: 58AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000316 AC: 79AN: 249656Hom.: 0 AF XY: 0.000274 AC XY: 37AN XY: 135064
GnomAD4 exome AF: 0.000452 AC: 659AN: 1458682Hom.: 0 Cov.: 32 AF XY: 0.000475 AC XY: 345AN XY: 725794
GnomAD4 genome ? AF: 0.000381 AC: 58AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29AN XY: 74418
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:4
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 10, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 04, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 06, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 31, 2022 | BS1, BP2, PP3 - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | RET: BS2 - |
not specified Uncertain:1Benign:3Other:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 26, 2016 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2021 | Variant summary: RET c.1946C>T (p.Ser649Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 251656 control chromosomes. The observed variant frequency is approximately 61 fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma phenotype (5.6e-06), strongly suggesting that the variant is benign. c.1946C>T has been reported in the literature in individuals affected with sporadic/familial Medullary Thyroid Carcinoma/Hirschsprung's disease and in some instances in unaffected family members when tested (example, Wiench_2001, Vierhapper_2004, Colombo-Benkmann_2008, deGroot_2006, Vaclavikova_2009, Waldman_2009, Erlic_2010, Innella_2020). These data do not allow any conclusion about variant significance. Multiple co-occurrences in trans with other pathogenic variant(s) have been reported in the citations ascertained above (example, RET c.1902C>G, p.Cys634Trp; RET c.1901G>A, p.Cys634Tyr; RET c.2410G>A, p.Val804Met; RET c.2410G>C, p.Val804Leu), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Colombo-Benkmann_2008). The most pronounced variant effect results in a mild transforming potential and constitutive TK activity, and stimulation of growth of NIH3T3 cells. This resulted in its classification as a level 1 RET variant, namely low penetrance of MTC, a relatively low aggressive potential of the disease (level 1), and rare further endocrinopathies. In summary, this was historically considered a "mild" mutation in MTC since penetrance seemed quite low, disease phenotype was milder than in MEN2/2A, and prognosis was good in patients with this variant; however, the interpretation changed when Erlic_2010 reported data strongly suggesting it is NOT pathogenic: 1) variant was incidentally found in the healthy sister of a p.C634Y MTC/PHEO patient during family testing for p.C634Y; 2) variant was found at significant frequencies in European and American normals. The non-pathogenicity of this variant is supported by the fact that in multiple reported MTC cases, it has co-occurred with true pathogenic variants, with reports that the two mutations together did not aggravate disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments but a majority concordance towards a benign/likely benign outcome (n=8) (VUS, n=6). Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 10, 2022 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2017 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been classified as DM in HGMD related to elevated basal serum calcitonin. It has been reported in 12 papers, with 2 related to Hirschprung disease. The comments suggest that it is not pathogenic. This variant is present at 0.05% in ExAC. It is classified in ClinVar with 1 star as Likely benign/Benign by Invitae and Children's Mercy Hospital, and as VUS by Ambry and ARUP. Variant occurs at greater frequency in population than expected for disorder - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2019 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 21, 2021 | - - |
Multiple endocrine neoplasia type 2A Benign:3
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 18, 2023 | This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | May 16, 2018 | - - |
Multiple endocrine neoplasia, type 2 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 18, 2022 | - - |
Appendicitis Uncertain:1
Uncertain significance, no assertion criteria provided | research | Klinik und Poliklinik für Kinderchirurgie, Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus | Dec 17, 2020 | - - |
Pheochromocytoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 15, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Elevated basal serum calcitonin Benign:1
Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Renal hypodysplasia/aplasia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 15, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Hirschsprung disease, susceptibility to, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 15, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Multiple endocrine neoplasia Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 15, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at