rs74799832

chr10-43121968-T-C

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: RET NM_020975 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:38
• Conservation: PhyloP100: 8.01

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant; Number of alleles below threshold, Median coverage is 33.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43121967-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38614. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	UniProt
RET	NM_020975.6	c.2753T>C	p.Met918Thr	missense_variant	16/20	ENST00000355710.8
RET	NM_020630.6	c.2753T>C	p.Met918Thr	missense_variant	16/19
RET	NM_001355216.1	c.1991T>C	p.Met664Thr	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.2753T>C	p.Met918Thr	missense_variant	16/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251478 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:38

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics Inc	Jul 24, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 11, 2022	PP4, PP5, PM1, PM2, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Karolinska University Hospital, Karolinska University Hospital	Jul 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	PerkinElmer Genomics	Oct 25, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Multiple endocrine neoplasia, type 2b Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 18, 2023	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]. -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2021	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. -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 13, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	May 21, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 07, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 11, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Nov 03, 2006	- -

Multiple endocrine neoplasia, type 2a Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 21, 2016	M918T is associated only with MEN2B phenotype. -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 13, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -

Medullary thyroid carcinoma Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Mar 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	3DMed Clinical Laboratory Inc	Aug 02, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jul 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 11, 2022	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. -

Multiple endocrine neoplasia type 4 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2014

- -

Pheochromocytoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 07, 1998

- -

Hirschsprung disease, susceptibility to, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomics England Pilot Project, Genomics England

-

- -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 26, 2022

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). 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: 8570194, 9242375, 16715139, 21810974). For these reasons, this variant has been classified as Pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 16, 2019

The RET c.2753T>C, p.Met918Thr variant has been reported in multiple patients diagnosed with multiple endocrine neoplasia type 2b (Carlson 1994, Jindrichova 2004), 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 (Bongarzone 1998, Santoro 1995). The variant is listed in the dbSNP variant database (rs74799832), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Exome Aggregation Consortium). The methionine at residue 918 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as 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. 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. 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. 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. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015; 25(6):567-610. -

Constipation;C0020534:Hypertelorism;C0020676:Hypothyroidism;C0039685:Tetralogy of Fallot;C0349588:Short stature;C0376480:Gingival overgrowth;C1836543:Thick vermilion border;C1844820:Joint hypermobility Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 08, 2014

- -

Multiple endocrine neoplasia, type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Thyroid carcinoma, sporadic medullary Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 07, 1998

- -

Familial medullary thyroid carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 17, 2018

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] -

Thyroid tumor Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.46

D

BayesDel_noAF

Pathogenic

0.42

Cadd

Pathogenic

27

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Benign

0.85

T;T

M_CAP

Pathogenic

0.34

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.78

D

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.92

D

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

D

GERP RS

5.4

Varity_R

0.96

gMVP

0.97

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs74799832; hg19: chr10-43617416; COSMIC: COSV60685905;