10-43113622-G-A

Position:

chr10-43113622-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_020975.6(RET):c.1826G>A(p.Cys609Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,148 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C609F) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24O:1

Conservation

PhyloP100: 8.13

Variant links:

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_020975.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-43113622-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 38284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 10-43113622-G-A is Pathogenic according to our data. Variant chr10-43113622-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6 linkuse as main transcript	c.1826G>A	p.Cys609Tyr	missense_variant	10/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.1826G>A	p.Cys609Tyr	missense_variant	10/20	5	NM_020975.6	P4	P07949-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248472

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134604

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:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460994

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726710

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2021	Published functional studies demonstrate a damaging effect: significantly reduced transforming activity (Ito 1997); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16715139, 22270996, 30763276, 20516206, 14633923, 18206480, 17021738, 18063059, 7907913, 9230192, 7849720, 15699703, 21986619, 9384613, 19472011, 27994876, 24705026, 10220148, 7595168, 18984779, 7633441, 20979234, 8901418, 12915470, 28647780, 29790872, 30927507, 31510104, 9498388, 12686527, 15531714, 10462620, 8855832, 31447099, 30787465, 33087929) -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 07, 2020	The RET c.1826G>A; p.Cys609Tyr variant (rs77939446) has been reported in multiple patients diagnosed with multiple endocrine neoplasia type 2A (MEN2A), familial medullary thyroid carcinoma (FMTC) and Hirschsprung disease, and is considered a variant of moderate risk by the American Thyroid Association (Wells 2015). The variant is listed in the ClinVar database (Variation ID: 13933) and is found on only one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant lies within a cysteine rich domain; pathogenic variants resulting in the loss of a cysteine residue are common in these repeats and are predicted to disrupt protein structure, resulting in aberrant activation of the RET protein (Amoresano 2005, Chappuis-Flament 1998, Ito 1997). Additionally, other amino acid substitutions at this codon (Arg, Gly, Phe, Ser, Trp) have been reported in individuals with MEN2A and FMTC and are considered pathogenic (Frank-Raue 2011, Paszko 2007, Romei 2010, Siegelman 1997). Based on available information, the p.Cys609Tyr variant is considered pathogenic. References: Amoresano A et al. Direct interactions among Ret, GDNF and GFRalpha1 molecules reveal new insights into the assembly of a functional three-protein complex. Cell Signal. 2005 Jun;17(6):717-27. Chappuis-Flament S et al. Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines. Oncogene. 1998 Dec 3;17(22):2851-61. Frank-Raue K et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat. 2011 Jan;32(1):51-8. Ito S et al. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype. Cancer Res. 1997 Jul 15;57(14):2870-2. Paszko Z et al. The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred's from Central Poland. Cancer Invest. 2007 Dec;25(8):742-9. Romei C et al. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol. 2010 Aug;163(2):301-8. Siegelman M et al. Rapid, nonradioactive screening for mutations in exons 10, 11, and 16 of the RET protooncogene associated with inherited medullary thyroid carcinoma. Clin Chem. 1997 Mar;43(3):453-7. Wells S et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015 25(6):567-610. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 18, 2022	PP1_strong, PP4, PP5, PM1, PS3_supporting, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 02, 2017	This variant is located at one of the hot spots for pathogenic variants associated with MEN 2A and FMTC. In the published literature, this variant has been reported in individuals with MEN 2A or FMTC (PMID: 7849720 (1994), 7907913 (1994), 9146685 (1997), 18206480 (2008)). It has also been reported in individuals with Hirschsprung disease (PMID: 7633441 (1995), 9384613 (1998), 9824583 (1998)). In a functional study, this variant had a deleterious effect on RET protein function (PMID: 9230192 (1997)). Based on the available information, this variant is classified as pathogenic. -

Multiple endocrine neoplasia type 2A

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3., this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function variants are associated with Hirschsprung disease (MIM#142623), while gain of function variants cause multiple endocrine neoplasia IIA (MEN2A, MIM#171400), multiple endocrine neoplasia IIB (MEN2B, MIM#162300), and medullary thyroid carcinoma (MTC, MIM#155240). A subset of RET cysteine variants, sometimes referred to as Janus variants, can lead to a partial loss-of-function phenotype, as well as to oncogenic effects (PMID: 22584710, OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in a missense hotspot region in the extracellular cysteine rich domain (PMID: 22584710, DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Alternative amino acid changes to arginine, phenylalanine, glycine, and serine, have been reported in individuals with MEN2A (PMID: 20979234, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with multiple endocrine neoplasia IIA (MEN2A), familial medullary thyroid carcinoma, and Hirschsprung disease (PMID: 20979234, PMID: 8733882, PMID: 7633441, ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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: 9230192, 16715139]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19472011, 27994876, 15858153, 21986619, 20979234, 18206480, 25810047]. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 08, 2018	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jul 22, 2019	- -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 13, 2016	- -

Multiple endocrine neoplasia, type 2

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 609 of the RET protein (p.Cys609Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma, and Hirschsprung disease (PMID: 19472011, 24617864). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13933). 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: 9230192, 9681851, 16715139, 21986619). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 04, 2018	The p.Cys609Tyr variant in RET (ClinVar variation ID# 13933) is a well-known, pa thogenic variant that causes multiple endocrine neoplasia type 2A (MEN2A) (Marqu ard 2015: ReneReviews). This variant has been reported in more than 15 families with a range of RET-associated presentations including MEN2A, and medullary thyr oid carcinoma (MTC), and Hirschsprung disease (Blaugrund 1994, Eng 1996, Decker 1998, de Groot 2005, Ahmed 2005, Quayle 2007, Calva 2009). The variant segregate d with the disease in at least 9 affected relatives (Calva 2009, Ahmed 2005). Ot her data supporting pathogenicity includes rarity in population databases (1/110 672 of European chromosomes, Genome Aggregation Database (gnomAD, http://gnomad. broadinstitute.org/; dbSNP rs77939446) and functional studies (Ito 1997, Mise 20 06). In summary, this variant meets criteria to be classified as pathogenic for MEN2A in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4; PP1_Stron g; PM2; PS3_Moderate; PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2023	Variant summary: RET c.1826G>A (p.Cys609Tyr) results in a non-conservative amino acid change in 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 248472 control chromosomes. c.1826G>A has been widely reported in the literature as a well-established disease causing variant in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma and in those with Hirschsprung disease (example, Balugrund_1994, Halling_1997, Decker_1998, Ahmed_2005, Fialkowski_2008, Vaclavikova_2012). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in enhanced cell cycle progression supported by demonstration of increased cell proliferation in-vivo and in-vitro (example, Mise_2006). The following publications have been ascertained in the context of this evaluation (PMID: 15858153, 7849720, 9498388, 10462620, 9230192, 16715139, 18206480, 21986619). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial medullary thyroid carcinoma

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jun 09, 2015	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 20, 2018	- -

Multiple endocrine neoplasia type 4

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Multiple endocrine neoplasia type 2B

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Hirschsprung disease, susceptibility to, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 20, 2024

- -

RET-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2024

The RET c.1826G>A variant is predicted to result in the amino acid substitution p.Cys609Tyr. This variant has previously been reported in individuals who have multiple endocrine neoplasia, familial medullary thyroid carcinoma and phaeochromocytoma who may also have Hirschsprung disease (Blaugrund et al. 1994. PubMed ID: 7849720. Vaciavikova et al. 2012. PubMed ID: 21986619; Muth et al. 2012. PubMed ID: 22270996). Reduced penetrance has been reported for p.Cys609Tyr and multiple other p.Cys609 variants. In addition, age-related penetrance and clinical phenotype variability have also been reported for RET p.Cys609 variants, including p.Cys609Tyr (Frank-Raue et al. 2011. PubMed ID: 20979234). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13933/). In summary, this variant is interpreted as pathogenic. -

Multiple endocrine neoplasia, type 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA, WITH HIRSCHSPRUNG DISEASE

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 28, 2017

- -

Medullary thyroid carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

The p.C609Y pathogenic mutation (also known as c.1826G>A), located in coding exon 10 of the RET gene, results from a G to A substitution at nucleotide position 1826. The cysteine at codon 609 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been identified in multiple MEN2A patients and families with Hirschsprung disease (HSCR1), familial medullary thyroid cancer (FMTC), and pheochromocytoma (Blaugrund JE et al. Hum. Mol. Genet. 1994 Oct;3(10):1895-7; Decker RA et al. Hum. Mol. Genet. 1998 Jan;7(1):129-34; Fialkowski EA et al. J. Pediatr. Surg. 2008 Jan;43(1):188-90; Vaclavikova et al. Pediatr. Surg. Int. 2012 Feb;28(2):123-8; Muth et al. World J. Surg. 2012 Jun;36(6):1389-94; Speak R et al. Endocrinol Diabetes Metab. Case Rep. 2016 Nov;2016; Giacché M et al. Hum Mutat, 2019 07;40:926-937). The American Thyroid Association Guidelines Task Force has provided recommendations for individuals with RET gene mutations (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 2A;C1833921:Familial medullary thyroid carcinoma

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

D;D;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.7

M;.;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-8.7

D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.99

MutPred

0.97

Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);

MVP

0.99

MPC

1.0

ClinPred

1.0

GERP RS

4.9

Varity_R

0.96

gMVP

1.0

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.

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