10-43119548-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong
The NM_020975.6(RET):c.2410G>A(p.Val804Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,605,504 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V804L) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
RET
NM_020975.6 missense
NM_020975.6 missense
Scores
7
9
3
Clinical Significance
Conservation
PhyloP100: 9.99
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 Pathogenic. Variant got 12 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr10-43119548-G-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.848
PP5
Variant 10-43119548-G-A is Pathogenic according to our data. Variant chr10-43119548-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119548-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RET | NM_020975.6 | c.2410G>A | p.Val804Met | 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.2410G>A | p.Val804Met | missense_variant | 14/20 | 5 | NM_020975.6 | ENSP00000347942 | P4 |
Frequencies
GnomAD3 genomes 0.0000986 AC: 15AN: 152138Hom.: 0 Cov.: 34
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:40
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 08, 2023 | In the published literature, the c.2410G>A variant has been noted to be enriched in MEN2 and FMTC patients in published patient screens (PMID: 15741265 (2005), 17316110 (2007), 17895320 (2007), 25624014 (2015), 26758973 (2016)). Increased kinase activity, altered substrate specificity, and resistance to some drugs have been observed in the published literature (PMID: 21454698 (2011)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 08, 2023 | The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant is statistically significantly enriched in affected patients as compared to ethnically matched controls. The American Thyroid Association has placed this variant into the ATA-MOD category, which includes the former levels A and B, for having a moderate risk of developing aggressive medullary thyroid carcinoma (MTC; see PMID: 25810047). This variant associates with disease in multiple families with medullary thyroid cancer and appears to occur de novo in one individual with MEN2B. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 21454698) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 27, 2022 | PP1_strong, PP4, PP5, PM6, PS4_moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jul 21, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 02, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2020 | Published functional studies demonstrate a damaging effect: increased transforming activity (Cosci et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15693160, 24336963, 20516206, 28951487, 17466010, 11732489, 24361808, 19958926, 20494215, 23468374, 8797874, 21810974, 20369307, 25501606, 10826520, 16507829, 24466223, 10876191, 11788682, 15184865, 27099842, 27814560, 27809725, 25903693, 28647780, 15386323, 28125075, 26556299, 19445625, 16955009, 16343097, 31159747, 9452077, 29590403, 30093976, 30936199, 31510104, 30763276, 29625052, 31447099, 23341727, 33615670, 31589614, 33361738, 11932300, 30624503, 30787465, 33087929) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 14, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 26, 2021 | DNA sequence analysis of the RET gene demonstrated a sequence change, c.2410G>A, in exon 14 that results in an amino acid change, p.Val804Met. This sequence change is a well-described pathogenic variant in the RET gene that has been reported in multiple families with medullary thyroid carcinoma (PMID: 7784092, 8797874, 9452077, 25440022, 10876191, 17895320, 11114642, 19958926). The American Thyroid Association categorizes this as a moderate-risk variant meaning that the risk for aggressive medullary thyroid cancer may be reduced in comparison with other pathogenic variants in the RET gene (PMID: 25810047). This sequence change has been described in the gnomAD database with a frequency of 0.02% in the Latino/Admixed American subpopulation (dbSNP rs79658334). The p.Val804Met change affects a highly conserved amino acid residue located in a domain of the RET protein that is known to be functional. The p.Val804Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Experimental studies have shown that this pathogenic sequence change affects the normal function of the RET protein (PMID: 20039896 21711375). Collectively these evidences indicate this variant is pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 13, 2023 | The RET c.2410G>A; p.Val804Met variant (rs79658334) has been described in individuals affected with multiple endocrine neoplasia type 2 (MEN2), and has shown to segregate with disease but with reduced penetrance compared to different pathogenic RET variants (Basaran 2015, Choi 2013, Elisei 2007, Fattoruso 1998, Feldman 2000, Fink 1996, Romei 2015). It is generally not associated with pheochromocytoma, parathyroid adenoma or hyperparathyroidism, and the American Thyroid Association describes individuals with this variant as having a moderate risk for medullary thyroid cancer (MTC) (Wells 2015). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 37102) and is observed in the general population at an overall frequency of 0.014% (36/259772 alleles) in the Genome Aggregation Database. It is estimated that the cumulative lifetime risk for MTC in individuals harboring this variant is 31% by age 50, 67% by age 60 and 87% by age 70 (Rich 2014), although penetrance has also been estimated to be as low as 4% (Loveday 2018). The valine at codon 804 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.716). Additionally, in vitro functional studies demonstrate increased cellular proliferation and tyrosine kinase activity, as well as a conferred resistance to selective kinase inhibitors (Carlomagno 2004, Castellone 2010, Cosci 2011, Machens 2011). Based on available information, this variant is considered pathogenic. References: Basaran M et al. Characterization of V804M-mutated RET proto-oncogene associated with familial medullary thyroid cancer, report of the largest Turkish family. J Endocrinol Invest. 2015 May;38(5):541-6. PMID: 25501606 Carlomango F et al. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene. 2004 Aug 12;23(36):6056-63. PMID: 15184865 Castellone M et al. A novel de novo germ-line V292M mutation in the extracellular region of RET in a patient with phaeochromocytoma and medullary thyroid carcinoma: functional characterization. Clin Endocrinol (Oxf). 2010 Oct;73(4):529-34. PMID: 20039896 Choi Y et al. A Case of medullary thyroid carcinoma with de novo V804M RET germline mutation. J Korean Med Sci. 2013; 28(1):156-9. PMID: 23341727 Cosci B et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011; 18(5):603-12. PMID: 21810974 Elisei R et al. RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab. 2007; 92(12):4725-9. PMID: 17895320 Fattoruso O et al. A GTG to ATG novel point mutation at codon 804 in exon 14 of the RET proto-oncogene in two families affected by familial medullary thyroid carcinoma. Hum Mutat. 1998; Suppl 1:S167-71. PMID: 9452077 Feldman G et al. Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation. Surgery. 2000; 128(1):93-8. PMID: 10876191 Fink M et al. Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. "Study Group Multiple Endocrine Neoplasia Austria (SMENA)". Int J Cancer. 1996; 69(4):312-6. PMID: 8797874 Loveday C et al. p.Val804Met, the most frequent pathogenic mutation in RET, confers a very low lifetime risk of medullary thyroid cancer. J Clin Endocrinol Metab. 2018 Mar 23. PMID: 29590403 Machens A et al. Germline RET sequence variation I852M and occult medullary thyroid cancer: harmless polymorphism or causative mutation? Clin Endocrinol (Oxf). 2011 Dec;75(6):801-5. PMID: 21711375 Rich T et al. Prevalence by age and predictors of medullary thyroid cancer in patients with lower risk germline RET proto-oncogene mutations. Thyroid. 2014 Jul;24(7):1096-106. PMID: 24617864 Romei C et al. Twenty years of lesson le - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jan 04, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | RET: PP1:Strong, PS3, PS4:Moderate - |
Multiple endocrine neoplasia type 2A Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 05, 2022 | _x000D_ Criteria applied: PS4, PM5_STR, PS2_MOD, PS3_SUP - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Jul 13, 2017 | This variant has been previously reported in patients from various ethnic origins with MTC and the variant has been shown to co-segregate with the disease by Romei C et al in 2015, Basaran MN et al in 2015, Fink M et al in 1996 and Fattoruso et al in 1998.This variant has been reported in the dbSNP database with identification number rs79658334 and in ExAC database with the allele frequency of 0.025%. In the Clin Var database , the clinical significance of this variant has been reported as pathogenic (RCV000148773.3) with respect to MEN2. In silico prediction tools(SIFT, LRT, MutationTaster, PolyPhen-2 and FATHMM) suggests that this variant is probably damaging to protein function. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 26, 2023 | This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24560924, 21810974, 21711375, 20039896, 15184865]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15386323, 34637071, 25501606, 21134561, 10876191, 11114642, 29590403, 25810047, 20497437]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | May 26, 2017 | This c.2410G>A (p.Val804Met) variant in the RET gene has been reported in multiple publications [PMID 8797874, 20369307, 21810974, 24361808, 23468374, 23341727, 11732489, 24336963, 19958926, 20494215]. This variant was reported in patients and segregating in multiple families with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma [PMID 8797874, 23468374, 23341727, 20369307, 19958926, 20494215]. In vitro analysis showed that this variant affect the function of the RET protein [PMID 21810974]. A different nucleotide change (c.2410G>C), affecting the same amino acid (p.Val804Leu) has also been reported in a patient with multiple endocrine neoplasia 2 [PMID 14718397]. This variant is highly conserved and while not validated for clinical use, computer-based algorithms predict this p.Val804Met change to be deleterious. This variant has been observed in 13 heterozygous individuals in the ExAC database (http://exac.broadinstitute.org/variant/10-43614996-G-A). It is thus classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 23, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Heidelberg University | Oct 13, 2023 | - - |
Multiple endocrine neoplasia, type 2 Pathogenic:5
| Pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 804 of the RET protein (p.Val804Met). This variant is present in population databases (rs79658334, gnomAD 0.02%). This variant has been reported to segregate with medullary thyroid carcinoma (MTC) in several families with reduced penetrance compared to other pathogenic variants in the RET gene (PMID: 8797874, 9452077, 10876191, 25501606, 19958926, 11114642, 12019403, 17895320, 25440022). The cumulative lifetime risk for MTC in individuals harboring this variant has been calculated to be 17% by age 40, 31% by age 50, 67% by age 60, and 87% by age 70 (PMID: 24617864). Genotype-phenotype correlations have been described (PMID: 25810047). ClinVar contains an entry for this variant (Variation ID: 37102). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RET function (PMID: 15184865, 20039896, 21711375). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 03, 2024 | This missense variant replaces valine with methionine at codon 804 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that the variant resulted in intermediate level of transforming activity on transfected cells in vitro (PMID: 21810974) and an intermediate increase in kinase activity over wild-type RET (PMID: 20039896), as well as selective resistance to tyrosine kinase inhibitors (PMID: 15184865). This variant has been reported in dozens of heterozygous individuals affected with medullary thyroid cancer (PMID: 8797874, 9452077, 10876191, 11114642, 15741265, 23341727, 24361808, 33167350) that is rarely accompanied by hyperparathyroidism and/or pheochromocytoma (PMID: 15386323, 17466010, 31510104) and 3 homozygous carriers affected with medullary thyroid cancer, including one with pheochromocytoma (PMID: 12019403, 15741265). This variant has been reported to confer moderate risks for medullary thyroid cancer (PMID: 25810047). Missense variants at codon 804, p.Val804Leu and p.Val804Met, have lower penetrance than other RET missense variants with cumulative medullary thyroid cancer penetrance probability by age from 3% at 30y, 17% at 40y, 31% at 50y, 67% at 60y, to 87% at 70y (PMID: 24617864). This variant also has been reported to segregate with disease in affected pedigrees (PMID: 9452077, 10826520, 10876191, 11114642, 12019403, 15386323, 17466010, 21134561, 24361808, 25501606). This variant has been identified in 36/263944 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 24, 2017 | The p.Val804Met variant in RET has been reported in > 6 probands with multiple e ndocrine neoplasia type 2 (MEN2), occurring de novo in at least one of these ind ividuals, and segregated with disease in over 25 affected relatives from 5 affec ted families (for examples, see Kasprzak 2001, Shifrin 2009, Shifrin 2010, Nakao 2013, Kihara 2014, Ercolino 2014). The majority of individuals with this varian t have familial medullary thyroid carcinoma, although at least 2 individuals wer e diagnosed with MEN2B. In vitro functional studies provide some evidence that t his variant may impact protein function (Machens 2011, Castellone 2010). The p.V al804Met variant has been classified by the American Thyroid Association as impa rting a moderate risk to developing aggressive medullary thyroid carcinoma (Well s 2015). It has also been reported by other clinical laboratories in ClinVar (Va riation ID #37102). In addition, this variant has been identified in 21/116790 o f European chromosomes by the Genome Aggregation Consortium (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs79658334). In summary, this variant meets criteri a to be classified as pathogenic for MEN2 in an autosomal dominant manner based on presence in multiple affected individuals and segregation studies. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This missense variant replaces valine with methionine at codon 804 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that the variant resulted in intermediate level of transforming activity on transfected cells in vitro (PMID: 21810974) and an intermediate increase in kinase activity over wild-type RET (PMID: 20039896), as well as selective resistance to tyrosine kinase inhibitors (PMID: 15184865). This variant has been reported in dozens of heterozygous individuals affected with medullary thyroid cancer (PMID: 8797874, 9452077, 10876191, 11114642, 15741265, 23341727, 24361808, 33167350) that is rarely accompanied by hyperparathyroidism and/or pheochromocytoma (PMID: 15386323, 17466010, 31510104) and 3 homozygous carriers affected with medullary thyroid cancer, including one with pheochromocytoma (PMID: 12019403, 15741265). This variant has been reported to confer moderate risks for medullary thyroid cancer (PMID: 25810047). Missense variants at codon 804, p.Val804Leu and p.Val804Met, have lower penetrance than other RET missense variants with cumulative medullary thyroid cancer penetrance probability by age from 3% at 30y, 17% at 40y, 31% at 50y, 67% at 60y, to 87% at 70y (PMID: 24617864). This variant also has been reported to segregate with disease in affected pedigrees (PMID: 9452077, 10826520, 10876191, 11114642, 12019403, 15386323, 17466010, 21134561, 24361808, 25501606). This variant has been identified in 36/263944 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Familial medullary thyroid carcinoma Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 23, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jan 31, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 804 of the RET protein (p.Val804Met). This variant is present in population databases (rs79658334, gnomAD 0.02%). This variant has been reported to segregate with medullary thyroid carcinoma (MTC) in several families with reduced penetrance compared to other pathogenic variants in the RET gene (PMID: 8797874, 9452077, 10876191, 25501606, 19958926, 11114642, 12019403, 17895320, 25440022). The cumulative lifetime risk for MTC in individuals harboring this variant has been calculated to be 17% by age 40, 31% by age 50, 67% by age 60, and 87% by age 70 (PMID: 24617864). Genotype-phenotype correlations have been described (PMID: 25810047). ClinVar contains an entry for this variant (Variation ID: 37102). In silico analysis supports that this missense variant does not alter protein structure/function. Experimental studies have shown that this missense change affects RET function (PMID: 15184865, 20039896, 21711375).The American Thyroid Association has designated alterations at this codon occurring without additional RET mutations as moderate risk mutations (Wells SA et al. Thyroid. 2015 Jun;25:567-610). For these reasons, this variant has been classified as Pathogenic. Pathogenic mutations in the RET gene cause Medullary thyroid carcinoma (MIM# 155240). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Apr 03, 2023 | This RET variant (rs79658334) is rare (<0.1%) in a large population dataset (gnomAD: 36/263944 total alleles; 0.014%; no homozygotes) and has been reported in ClinVar. This variant has been shown to segregate with medullary thyroid carcinoma (MTC) in several families with reduced penetrance compared to other pathogenic variants in the RET gene. This variant is defined by the American Thyroid Association as a level A variant, which represents the lowest risk group for developing MTC. It is estimated that the cumulative lifetime risk for MTC in individuals harboring this variant is 31% by age 50, 67% by age 60 and 87% by age 70, although penetrance has also been estimated to be as low as 4%. In vitro functional studies demonstrate this substitution leads to increased cellular proliferation and increased tyrosine kinase activity. This is supported by structural analysis that indicates the alteration changes the conformation of the ATP binding pocket, making it more permissive for binding ATP, and thus enhancing RET activation. We consider c.2410G>A to be pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 04, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This sequence change replaces Valine with Methionine at codon 804 of the RET protein. The valine residue is highly conserved among species in the Protein kinase domain of the protein. There is a small physicochemical difference between valine and methionine (Grantham Score 21). This variant has been described in several families with multiple endocrine neoplasia type 2 and medullary thyroid carcinoma (MTC) (PMID 8797874, 23468374, 9452077, 10876191, 25501606). This variant is listed in population databases at a very low frequency (rs79658334, ExAC 0.03%). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may have a deleterious impact on protein function. Moreover, this prediction has been confirmed experimentally (PMID: 20039896,21711375,) .The mutation database ClinVar contains multiple entries for this variant (Variation ID:37102). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 13, 2024 | The p.V804M mutation (also known as c.2410G>A), located in coding exon 14 of the RET gene, results from a G to A substitution at nucleotide position 2410. The valine at codon 804 is replaced by methionine, an amino acid with highly similar properties. This mutation has been described in an Austrian family with familial medullary thyroid carcinoma (FMTC) and was present in both affected and unaffected family members (Fink M et al. Int. J. Cancer. 1996 Aug;69:312-6). This alteration has also been reported as a confirmed de novo mutation in the setting of new MTC disease in a family (Choi YS et al. J. Korean Med. Sci. 2013 Jan;28:156-9; Nakao KT et al. Head Neck. 2013 Dec;35:E363-8). This alteration has been reported in individuals with homozygous state (Lesueur F et al. J Clin Endocrinol Metab, 2005 Jun;90:3454-7; Lecube A et al. Surgery, 2002 May;131:509-14). A few studies have suggested that in addition to the association with MTC, mutations at codon 804 may be associated with papillary thyroid carcinoma (Brauckhoff M et al. Langenbeck's Arch Surg. 2002 Oct;387:201-3; Shifrin AL et al. Surgery. 2009 Dec;146:998-1005; Basaran MN et al. J. Endocrinol. Invest. 2015 May;38:541-6). The p.V804M mutation has also been reported in families with pheochromocytomas (Recasens M et al. Clin. Endocrinol. (Oxf). 2007 Jul;67:29-33). In vitro analyses demonstrated that cells transfected with the p.V804M alteration produced an intermediate number of focus formation units and an intermediate number of colonies when compared to wild-type, but did not show any significant difference from wild-type with respect to the proliferation rate (Cosci B et al. Endocr. Relat. Cancer. 2011 Sep;18:603-12). Additional in vitro analysis shows that the RET p.V804M alteration has a marked increase in kinase activity over wild-type (Machens A et al. Clin. Endocrinol. (Oxf). 2011 Dec;75:801-5). This is supported by structural analysis that indicates the alteration changes the conformation of the ATP binding pocket, making it more permissive for binding ATP, and thus enhancing RET activation (George Priya Doss C et al. Mol Biosyst. 2014 Mar;10:421-36). Disease expression of mutations at codon 804 have been shown to be highly variable, even within the same family (Feldman GL et al. Surgery. 2000 Jul;128:93-8; Frohnauer MK and Decker RA. Surgery. 2000 Dec;128:1052-7). The American Thyroid Association has designated alterations at this codon occurring without additional RET mutations as moderate risk mutations (Wells SA et al. Thyroid. 2015 Jun;25:567-610). Based on the available evidence, p.V804M is classified as a pathogenic mutation with moderate risk. - |
RET-related disorder Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 04, 2022 | ACMG classification criteria: PS3 supporting, PM5 moderated, PM6 moderated, PP3 supporting - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 02, 2024 | The RET c.2410G>A variant is predicted to result in the amino acid substitution p.Val804Met. This variant has been reported in individuals with medullary thyroid carcinoma (reported as c804 in Frohnauer and Decker. 2000. PubMed ID:11114642; Choi et al. 2013. PubMed ID: 23341727; Kasprzak et al. 2001. PubMed ID: 11732489; Rothberg et al. 2009. PubMed ID: 19445625). However, some reports have described this variant as having low penetrance and only causing carcinoma in the homozygous state (Lecube et al. 2002. PubMed ID 12019403; Lesueur et al. 2005. PubMed ID 15741265). Functional studies show the p.Val804Met variant results in slightly higher growth and transformation rates compared to wild type RET (Cosci et al. 2011. PubMed ID: 21810974). Notably, an alternate substitution of this amino acid (p.Val804Leu) has also been reported in individuals with thyroid cancer (Kruckeberg and Thibodeau. 2004. PubMed ID 14718397; Table S1 in Currás-Freixes et al. 2015. PubMed ID 26269449; Pasini et al. 1997. PubMed ID 9242375). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. This variant is classified as pathogenic/likely pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37102/). Based on the available information, this variant is interpreted as pathogenic. - |
MEN2 phenotype: Unclassified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 14, 2023 | Variant summary: RET c.2410G>A (p.Val804Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 232600 control chromosomes (gnomAD). This variant has been reported to have a variable penetrance as the most frequently altered codon in multiple patients with features of FMTC (Familial Medullary Thyroid Cancer) and CCH (C-cell hyperplasia). c.2410G>A has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2, C-cell hyperplasia, and adrenocortical carcinoma (examples: Fink_1996, Miyauchi_1999, Ercolino_2014, Raygada_2020, and Alzahrani_2022). At-least one publication reported this variant as a de novo occurrence (Miyauchi_1999). These data indicate that the variant is very likely to be associated with disease. A pathogenic co-occurrence (MSH2 c.211+1G>T) have been reported in at-least one report (Raygada_RET_MG_2020). Multiple publications report experimental evidence evaluating an impact on protein function. These studies showed the variant moderately increased transforming activity (Cosci_2011) and increased kinase activity compared to WT (Plaza-Menacho_2011). Other variants affecting the same amino acid are reported as associated with Thyroid cancer and Multiple endocrine neoplasia 2 in HGMD. Twenty-six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Ovarian cancer Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1275808:Congenital central hypoventilation;C1619700:Renal hypodysplasia/aplasia 1;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Hirschsprung disease, susceptibility to, 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 07, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at