10-43119694-C-G
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6
The NM_020975.6(RET):c.2556C>G(p.Ile852Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,613,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00023 ( 0 hom. )
Consequence
RET
NM_020975.6 missense
NM_020975.6 missense
Scores
3
11
5
Clinical Significance
Conservation
PhyloP100: 0.525
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.806
BP6
Variant 10-43119694-C-G is Benign according to our data. Variant chr10-43119694-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 24955.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=13}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RET | NM_020975.6 | c.2556C>G | p.Ile852Met | missense_variant | 14/20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RET | ENST00000355710.8 | c.2556C>G | p.Ile852Met | missense_variant | 14/20 | 5 | NM_020975.6 | ENSP00000347942.3 |
Frequencies
GnomAD3 genomes 0.000112 AC: 17AN: 152206Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000175 AC: 44AN: 250818Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135778
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GnomAD4 exome AF: 0.000225 AC: 329AN: 1461236Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 156AN XY: 726936
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GnomAD4 genome 0.000112 AC: 17AN: 152324Hom.: 0 Cov.: 34 AF XY: 0.000107 AC XY: 8AN XY: 74480
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:16Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:5
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RET p.I852M variant was identified in multiple individuals with multiple endocrine neoplasia type 2, an individual with pituitary adenoma, an individual with breast cancer and two individuals with medullary thyroid cancer (Joshi_2016_PMID: 26876062; Machens_2011_PMID: 21711375; Guerrero-Pérez_2019_PMID: 31431315; Mathiesen_2017_PMID: 27809725; Rich_2019_PMID: 31300450; Demeester _2001_PMID: 11295841; Castinetti _2014_PMID: 24745698). The p.I852M variant was found to segregate with disease in a father and two sons with multiple endocrine neoplasia type 2, however all three affected individuals also carried the RET p.C634Y variant known to be pathogenic (Joshi_2016_PMID: 26876062). In a separate family, this variant was not shown to segregate with medullary thyroid cancer (Machens_2011_PMID: 21711375). The variant was identified in dbSNP (ID: rs377767426) and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and three other laboratories). The variant was identified in control databases in 49 of 282156 chromosomes at a frequency of 0.0001737 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.I852 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however this information is not predictive enough to assume pathogenicity. In vitro functional studies have demonstrated that this variant increases protein activation and phosphorylation activity compared to wildtype (Machens_2011_PMID: 21711375). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 09, 2024 | The RET c.2556C>G (p.Ile852Met) variant has been reported in the published literature in individuals with MEN2 syndrome (PMIDs: 26876062 (2016), 24745698 (2014)), medullary thyroid cancer (MTC) (PMIDs: 28578594 (2017), 27525386 (2016), 21711375 (2011), 11295841 (2001)), pituitary adenoma/paraganglioma (PMID: 31431315 (2019)), endometrial, testicular, and lung cancer (PMID: 36451132 (2022)). This variant has also been observed in asymptomatic carriers (PMID: 21711375 (2011), 11295841 (2001)). Functional studies indicate this variant has a weak activating effect on RET transforming activity (PMID: 21711375 (2011)). The frequency of this variant in the general population, 0.00034 (17/50574 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | RET: PS3:Supporting - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 12, 2024 | Reported in a family with multiple endocrine neoplasia type 2A (MEN2A), co-segregating with a known pathogenic RET variant (PMID: 26876062); Published functional studies demonstrate reduced phosphorylation activity (PMID: 21711375); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16849421, 19522827, 21479187, 31431315, 29625052, 27930734, 29641532, 27809725, 26876062, 27525386, 24745698, 29341155, 29433789, 26556299, 29656518, 29020875, 28578594, 30349395, 35573754, 35210353, 31019283, 31043326, 33812987, 36451132, 11295841, 23527089, 21711375, 37975407, 14633923, 38637882, 35150601) - |
| Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Multiple endocrine neoplasia, type 2 Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 23, 2024 | This missense variant replaces isoleucine with methionine at codon 852 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study reported moderate transforming ability and auto-phosphorylation for this variant in cell culture (PMID: 21711375). This variant has been reported in individuals affected with MEN2 (PMID: 24745698, 26876062, 27809725), medullary thyroid carcinoma (PMID: 11295841, 21711375, 27525386), non-small cell lung cancer (PMID: 26556299), or pituitary adenoma with paraganglioma (PMID: 31431315). However, additional carriers in two carrier families were primarily asymptomatic without reported C-cell hyperplasia, medullary thyroid cancer, pheochromocytoma, or paraganglioma (PMID: 11295841, 21711375). In two affected carriers, a germline or somatic pathogenic co-variant was identified that explained the disease phenotype (PMID: 26876062, 28578594). This variant has been identified in 49/282156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 26, 2022 | The heterozygous variant c.2556C>G detected in exon 14 of the RET gene is a missense change resulting in an amino acid substitution from an Isoleucine to a Methionine at codon 852, p.(Ile852Met). This variant occurs at a moderately conserved within the Protein kinase domain. This variant is recorded in ClinVar as of uncertain significance (twice) and pathogenic (once), but has not been reported in the LOVD database. This variant was identified in individuals with medullary thyroid cancer, however it is unclear whether it segregates with disease (Machens et al, Clin Endocrinol (Oxf) (2011) 75(6):801-5; Demeester et al, Hum Mutat (2001) 17(4):354). It has also been reported to co-segregate with a pathogenic RET variant (p.Cys634Tyr) in a family (a father and his 2 sons) with multiple endocrine neoplasia type 2A (MEN2A) (Joshi et al, Head Neck. (2016) 38 Suppl 1:E1881-5). In vitro studies show that this variant is weakly activating compared to known pathogenic variants (Machens et al, Clin Endocrinol (Oxf) (2011) 75(6):801-5). This variant is observed at allele frequencies less than 0.029% in population databases (ESP and gnomAD), indicating it is not a common benign variant in these populations. In silico protein prediction programs are inconsistent regarding the effect of this variant on protein structure and function. Based on current knowledge, this is an unclassified (Class 3) variant and predictive testing is not available. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 03, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 852 of the RET protein (p.Ile852Met). This variant is present in population databases (rs377767426, gnomAD 0.03%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2 (MEN2A) and medullary thyroid cancer and non-small cell lung cancer (PMID: 11295841, 21711375, 24745698, 26556299, 26876062, 27525386, 28578594). ClinVar contains an entry for this variant (Variation ID: 24955). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RET function (PMID: 21711375). 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. - |
Multiple endocrine neoplasia type 2B Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | The p.I852M variant (also known as c.2556C>G) is in exon coding 14 of the RET gene. This variant results from a C to G substitution at nucleotide position 2556. The isoleucine at codon 852 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with multiple endocrine neoplasia type 2 (MEN 2), but conversely has also been reported in many unaffected individuals (Demeester R et al. Hum. Mutat. 2001 Apr;17:354; Machens A et al. Clin. Endocrinol. (Oxf). 2011 Dec;75:801-5; Guerrero-Pérez F et al. Eur. J. Intern. Med., 2019 Nov;69:14-19; Internal Ambry Data). Machens A et al. performed functional analyses on cells transfected with the p.I852M variant, which revealed proliferation rates, transforming capacities, and migratory activities similar to cells with a known pathogenic mutation (RET p.V804M). This alteration has also been reported in cis with a pathogenic RET mutation (p.C364Y) in a male with medullary thyroid cancer (MTC) at age 45, bilateral pheochromocytomas, and mild primary hyperparathyroidism (Joshi RR et al. Head Neck. 2016 Apr;38:E1881-5). Two sons of this individual were also found to carry both RET alterations; one with C-cell hyperplasia at prophylactic thyroidectomy, and another with MTC at age 7. This alteration was also detected in conjunction with a somatic RET alteration (c.1895_1910delCAGC) in an individual with medullary thyroid cancer at age 69 (Mathiesen JS et al. Thyroid. 2017 Aug;27:1103-1104). This amino acid position is well conserved in available vertebrate species. In addition, the in-silico prediction for this alteration showed pathogenic computational verdict based on 8 pathogenic predictions from DANN, DEOGEN2, FATHMM-MKL, LIST-S2, M-CAP, MutationTaster, REVEL and SIFT vs 5 benign predictions from BayesDel_addAF, EIGEN, MVP, MutationAssessor and PrimateAI. There is a ClinVar entry for this variant with two stars and 5 submissions, all of which describe it as of uncertain significance. - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 17, 2020 | DNA sequence analysis of the RET gene demonstrated a sequence change, c.2556C>G, in exon 14 that results in an amino acid change, p.Ile852Met. This sequence change has been described in the gnomAD database with a frequency of 0.03% in the European sub-population (dbSNP rs377767426). The p.Ile852Met change has been reported in several individuals with medullary thyroid cancer and lung cancer, and one individual with multiple endocrine neoplasia type 2 (PMID: 11295841, 21711375, 26556299, 28578594, 27525386, 24745698). The p.Ile852Met change affects a moderately conserved amino acid residue located in a domain of the RET protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile852Met substitution. In vitro functional studies have demonstrated that this sequence change may increase RET kinase activity (PMID: 21711375). Due to these contrasting evidences, the clinical significance of the p.Ile852Met change remains unknown at this time. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 21, 2023 | Variant summary: RET c.2556C>G (p.Ile852Met) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 250818 control chromosomes. The observed variant frequency is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 phenotype (3.7e-05), suggesting that the variant is either not highly penetrant or benign. c.2556C>G has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/medullary thyroid carcinoma (e.g., Demeester_2001, Machens_2011, Castinetti_2014, Joshi_2016, Sherman_2016, Mathiesen_2017). However the variant was not found to clearly segregate with disease in several of the families reported in the literature (e.g., Demeester_2001, Machens_2011, Mathiesen_2017). Additionally, a co-occurrence with another pathogenic germline variant was reported (RET c.1901G>A, p.Cys634Tyr; Joshi_2016), and co-occurring somatic RET variants have been reported in several affected individuals (e.g., Sherman_2016, Mathiesen_2017), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant leads to an increased proliferation rate and transforming potential, similar to a known pathogenic variant, as well as increased phosphorylation activity in vitro (e.g., Machens_2011). The following publications have been ascertained in the context of this evaluation (PMID: 24745698, 26876062, 21711375, 26556299, 27525386, 28578594, 11295841). Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014: 7 submitters classified the variant as uncertain significance and 1 submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Multiple endocrine neoplasia type 2A Uncertain:1Benign:1
| 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 16, 2017 | - - |
Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 08, 2024 | - - |
Hirschsprung disease, susceptibility to, 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 05, 2023 | - - |
RET-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 14, 2023 | The RET c.2556C>G variant is predicted to result in the amino acid substitution p.Ile852Met. This variant has been reported in the heterozygous state in individuals with medullary thyroid cancer and non-small cell lung cancer; however, pathogenicity was not established with segregation or functional studies (Demeester et al. 2001. PubMed ID: 11295841; Machens et al. 2011. PubMed ID: 21711375; Schrader et al. 2016. PubMed ID: 26556299). This variant was also reported to co-segregate with a pathogenic RET variant in a family with multiple endocrine neoplasia type 2A (Joshi et al. 2016. PubMed ID: 26876062). To our knowledge this variant has not been reported in association with any congenital abnormalities of the kidney or urinary tract. This variant is reported in 0.029% of alleles in individuals of South Asian descent in gnomAD and is interpreted as uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/24955/?new_evidence=true). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary cancer-predisposing syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 29, 2022 | 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. - |
Computational scores
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AlphaMissense
Benign
BayesDel_addAF
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Uncertain
CADD
Uncertain
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Uncertain
DEOGEN2
Uncertain
D;.
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Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
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D;D
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T
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at