dbSNP rs74799832: RET:p.Met918Thr (chr10-43121968-T-C) – ACMG Classification: Pathogenic (14 pts)

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]

RET links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 10-43121968-T-C is Pathogenic according to our data. Variant chr10-43121968-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43121968-T-C is described in Lovd as [Pathogenic]. Variant chr10-43121968-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.2753T>C	p.Met918Thr	missense_variant	Exon 16 of 20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 link	c.2753T>C	p.Met918Thr	missense_variant	Exon 16 of 20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251478

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:38

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:13

Nov 29, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 27, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PP5, PM1, PM2_moderate, PS3, PS4_moderate -

Jul 03, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RET c.2753T>C, p.Met918Thr variant (rs74799832, ClinVar Variation ID 13919), has been reported in multiple patients diagnosed with multiple endocrine neoplasia type 2b (Carlson 1994, Jindrichova 2004, Zendran 2020), co-segregated with affected family members, or occurred as a de novo alteration (Carlson 1994) and has been reported to confer high risk (Wells 2015). Functional characterization of the variant protein indicates an increase in basal auto-phosphorylation that is further enhanced upon growth factor stimulation, with altered target specificity compared to wildtype protein (Santoro 1995, Bongarzone 1998). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.91). Based on available information, this variant is considered to be pathogenic. References: Bongarzone I et al. Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation. Oncogene. 1998; 16(18):2295-301. PMID: 9620546. Carlson K et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A. 1994; 91(4):1579-83. PMID: 7906417 Jindrichova S et al. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol. 2004; 183(2):257-65. PMID: 15531714. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995; 267(5196):381-3. PMID: 7824936. Wells SA Jr et al. (2015) Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015; 25(6):567-610. PMID: 25810047. Zendran I et al. MEN2B syndrome - paediatric case report. Pediatr Endocrinol Diabetes Metab. 2020;26(4):211-215. English. PMID: 33191720. -

Jul 24, 2019

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Widely published variant reported to account for 95% of MEN2B cases. The best available variant frequency is uninformative because there are too few occurrences in population data. Found in multiple symptomatic patients. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Multiple de novo cases reported in the literature. In familial cases, variant segregates with disease. -

Jan 13, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 19, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Most common RET variant reported in association with MEN2B (Carlson 1994, Eng 1996, Brauckhoff 2004, Wray 2008); Published functional studies demonstrate a damaging effect: increased transforming ability, cellular proliferation, and tyrosine phosphorylation (Pasini 1997, Cosci 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10679286, 8570194, 30763276, 20516206, 15517484, 22359510, 10369718, 26843961, 23225389, 30660595, 18252215, 19826964, 11720239, 21765987, 9242375, 21810974, 7906417, 24336963, 23660265, 26294908, 23660872, 8918855, 7824936, 27807060, 27539324, 17963006, 29182461, 17540634, 19169500, 29396759, 16481266, 9541448, 18631354, 17576593, 17848262, 16808642, 26084817, 31510104, 29625052, 34308366, 33268590, 32561571, 8909322, 9706252, 33191720, 30624503, 32546069, 14633923) -

Multiple endocrine neoplasia type 2B

Pathogenic:9

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 18, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16715139, 9242375, 21810974]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7906417, 34629742, 29656518, 34881033, 25810047]. -

May 21, 2023

Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM6_VeryStrong+PS3+PS4+PP4+PM2_Supporting -

Aug 11, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 08, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RET c.2753T>C (p.Met918Thr) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of 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 4e-06 in 251618 control chromosomes. c.2753T>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2B (example, Carlson_1994, Elisei_2007, Hofstra_1994). These data indicate that the variant is very likely to be associated with disease. Multiple publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significant increase in tyrosine kinase activity resulting in a transforming activation of the RET proto-oncogene (example, Borrello_1995). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

May 23, 2023

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 03, 2006

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Multiple endocrine neoplasia type 2A

Pathogenic:3

Oct 21, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

M918T is associated only with MEN2B phenotype. -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2020

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Jul 01, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 10, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM6_VeryStrong, PS4, PP3_Moderate, PP1, PM2_Supporting, PS3_Supporting c.2753T>C, located in exon 16 of the RET gene, is predicted to result in the substitution of mehionine by threonine at codon 918, p.(Met918Thr). This variant is not present in the gnomAD v2.1.1 database (non-cancer data set)(PM2_Supporting). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.91) suggests a deleterious effect on protein function according to Pejaver 2022 thresholds (PMID: 36413997)(PP3_Moderate). This variant has been reported in the ClinVar database (1x likely pathogenic, 36x pathogenic) and in LOVD (5x pathogenic). Functional assays have demonstrated that RET p.(Met918Thr) induces autophosphorylation of tyrosine residues and transformation activity in fibroblasts (PMID:16715139, PMID: 9242375, PMID:10445857)(PS3_Supporting). It has been reported as de novo in multiple patients with no family history (PMID: 15517484, PMID: 26084817, PMID: 21765987)(PM6_Very Strong). This variant has been reported in association with multiple endocrine neoplasia type 2 (MEN2B), 90% of all MEN 2B mutations occur in codon 918, and familial medullary thyroid cancer patients and nit segregates in several families fulfilling RET phenotype (PMID: 15517484, PMID: 26084817, PMID 22992277, PMID: 34881033)(PS4, PP1). Based on currently available information, c.2753T>C is classified as a pathogenic variant to ACMG guidelines and the American Thyroid Association guidelines for the management of medullary thyroid carcinoma (PMID: 25810047). -

Mar 11, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M918T pathogenic mutation (also known as c.2753T>C), located in coding exon 16 of the RET gene, results from a T to C substitution at nucleotide position 2753. The methionine at codon 918 is replaced by threonine, an amino acid with similar properties. This mutation is located in the catalytic core of the tyrosine kinase domain, within a highly conserved region of the RET protein. This mutation was first described in 58 individuals with a clinical diagnosis of multiple endocrine neoplasia type 2B (MEN2B) (Carlson KM et al. Proc. Natl. Acad. Sci. U.S.A. 1994;91(4):1579-83), and has since been well described in numerous other affected individuals (Choi S et al. PLoS Genet. 2012;8(2):e1002420; Hedayati M et al. J Thyroid Res. 2011;2011:264248; Smith V et al. Gut. 1999 Jul;45(1):143-6). In another study, this mutation was described in 95% (75/79) of MEN2B families (Eng C et al. JAMA 1996;276(19):1575-9). Per the revised American Thyroid Associated guidelines, individuals with alterations at codon 918 in the RET gene are at highest risk for MTC with recommended screenings and/or surgical interventions beginning in early childhood (Wells SA et al. Thyroid 2015 Jun; 25(6):567-610). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hirschsprung disease, susceptibility to, 1

Pathogenic:2

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial medullary thyroid carcinoma

Pathogenic:2

Dec 23, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 17, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 7906417, 17540634, 8570194, 19169500, 22359510, 21810974, 23660872, 24336963, 21765987] -

Constipation;C0020534:Hypertelorism;C0020676:Hypothyroidism;C0039685:Tetralogy of Fallot;C0349588:Short stature;C0376480:Gingival overgrowth;C1836543:Thick vermilion border;C1844820:Joint hypermobility

Pathogenic:1

Dec 08, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pheochromocytoma

Pathogenic:1

May 07, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Thyroid carcinoma, sporadic medullary

Pathogenic:1

May 07, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Multiple endocrine neoplasia, type 2

Pathogenic:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 918 of the RET protein (p.Met918Thr). This variant is present in population databases (rs74799832, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant multiple endocrine neoplasia type 2 (PMID: 7906417, 8918855, 16715139, 20516206, 27539324). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13919). 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: 8570194, 9242375, 16715139, 21810974). For these reasons, this variant has been classified as Pathogenic. -

Medullary thyroid carcinoma

Pathogenic:1

Aug 02, 2017

3DMed Clinical Laboratory Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RET-related disorder

Pathogenic:1

Feb 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RET c.2753T>C variant is predicted to result in the amino acid substitution p.Met918Thr. This variant has previously been reported to be causative for multiple endocrine neoplasia type 2B, medullary thyroid carcinoma, and pheochromocytoma (Carlson et al. 1994. PubMed ID: 7906417; Hedayati et al. 2011. PubMed ID : 21765987; de Cubas et al. 2013. PubMed ID : 23660872; http://www.arup.utah.edu/database/MEN2/). This variant was also shown in vitro to have transforming ability (Pasini et al. 1997. PubMed ID: 9242375; Cosci et al. 2011. PubMed ID: 21810974). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13919/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

T;T

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

1.7

L;L

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.99

Loss of MoRF binding (P = 0.1062);Loss of MoRF binding (P = 0.1062);

MVP

0.97

MPC

0.84

ClinPred

1.0

GERP RS

5.4

Varity_R

0.96

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs74799832

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over