Submissions for variant NM_020975.6(RET):c.2556C>G (p.Ile852Met)

gnomAD frequency: 0.00011  dbSNP: rs377767426

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204335	SCV000261072	uncertain significance	Multiple endocrine neoplasia, type 2	2022-11-03	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000566408	SCV000674738	likely benign	Hereditary cancer-predisposing syndrome	2022-03-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Counsyl	RCV000662415	SCV000784850	uncertain significance	Multiple endocrine neoplasia, type 2a	2017-01-16	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755693	SCV000883124	uncertain significance	Multiple endocrine neoplasia, type 2b	2018-11-21	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818176	SCV002065505	uncertain significance	not specified	2020-02-17	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV001354419	SCV002599832	uncertain significance	not provided	2023-08-10	criteria provided, single submitter	clinical testing	Reported in a family with multiple endocrine neoplasia type 2A (MEN2A), co-segregating with a known pathogenic RET variant (Joshi et al., 2016); Observed in several individuals with medullary thyroid cancer or C-cell hyperplasia (Demeester et al., 2001; Machens et al., 2011; Machens et al., 2018), though in two patients, a RET activating variant was detected in the medullary thyroid tumor, which may have been responsible for the cancer development (Sherman et al., 2016; Mathiesen et al., 2017); Observed in individuals with Hirschsprung disease, pheochromocytoma, or glioma (Rusmini et al., 2013; Castinetti et al., 2014; Huang et al., 2018), as well as in a healthy control (Pritchard et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate reduced phosphorylation activity (Machens et al., 2011); This variant is associated with the following publications: (PMID: 23527089, 16849421, 11295841, 19522827, 21479187, 26876062, 31431315, 29625052, 27930734, 29641532, 27809725, 27525386, 24745698, 29341155, 29433789, 26556299, 29656518, 29020875, 28578594, 30349395, 35573754, 35210353, 31019283, 31043326, 21711375, 14633923, 33812987, 36451132)
Genetics and Molecular Pathology, SA Pathology	RCV000204335	SCV002761439	uncertain significance	Multiple endocrine neoplasia, type 2	2022-05-26	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001354419	SCV002774855	uncertain significance	not provided	2021-07-16	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000755693	SCV004015162	uncertain significance	Multiple endocrine neoplasia, type 2b	2023-07-07	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV000662415	SCV004018076	likely benign	Multiple endocrine neoplasia, type 2a	2023-04-18	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818176	SCV004029620	uncertain significance	not specified	2023-07-21	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003466870	SCV004208666	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-10-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924853	SCV004746919	uncertain significance	RET-related condition	2023-12-14	criteria provided, single submitter	clinical testing	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354419	SCV001549032	uncertain significance	not provided		no assertion criteria provided	clinical testing	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.