10-43113654-T-C

Position:

• chr10-43113654-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):​c.1858T>C​(p.Cys620Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,120 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. C620F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 6.52

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43113655-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 10-43113654-T-C is Pathogenic according to our data. Variant chr10-43113654-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43113654-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.1858T>C	p.Cys620Arg	missense_variant	10/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1858T>C	p.Cys620Arg	missense_variant	10/20	5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461120 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726794

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2023	The RET c.1858T>C, p.Cys620Arg variant (rs77316810) is reported in the literature in multiple individuals affected with multiple endocrine neoplasia type 2A (MEN2A) and/or familial medullary thyroid carcinoma (FMTC) (Donis-Keller 1993, Boedeker 2009, Hedayati 2011, Vaclavikova 2012). This variant is also reported in ClinVar (Variation ID: 13915). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.897). Based on the above information, the variant is classified as pathogenic. References: Boedeker CC et al. Head and neck paragangliomas in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2009 Jun;94(6):1938-44. PMID: 19336503. Donis-Keller H et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993 Jul;2(7):851-6. PMID: 8103403. Hedayati M et al. Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma. J Thyroid Res. 2011:264248. PMID: 21765987. Vaclavikova E et al. Hirschsprung's disease and medullary thyroid carcinoma: 15-year experience with molecular genetic screening of the RET proto-oncogene. Pediatr Surg Int. 2012 Feb;28(2):123-8. PMID: 21986619. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2022	Published functional studies demonstrate a damaging effect: auto-kinase and phoshorylation activities, increased proliferation activity, impaired protein maturation, decreased cell surface expression, mouse model demonstrating tumorigenesis and intestinal hypoganglionosis (Ito 1997, Chappuis-Flament 1998, Arighi 2004, Carniti 2006, Yin 2007); Not observed at significant frequency in large population cohorts (gnomAD); 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: 9384613, 9067749, 9230192, 7835899, 18209889, 19853744, 17514199, 17623957, 21986619, 23744765, 30763276, 16158949, 20979234, 29020875, 12711285, 33340421, 7633441, 16565500, 19336503, 18206480, 15355438, 21765987, 18062802, 20152359, 7881414, 22584707, 20516206, 9681852, 7874109, 25694125, 9090527, 9824583, 17021738, 22584721, 25810047, 7915165, 17372903, 18063059, 8909322, 17316110, 14715928, 9879991, 22897442, 31510104, 31447099, 32179705, 33178136, 30787465, 34987852, 17188172, 11955539, 30349395, 27207748, 11564857, 27847096, 19469690, 8918855, 33754314, 17102091, 15744028, 10790203, 14633923) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	May 31, 2018	- -

Multiple endocrine neoplasia type 2A Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 22, 2024	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9230192, 17102091]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 33754314, 7881414, 37046785, 24616415, 25810047]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 04, 2013	- -
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	- -

Hirschsprung disease, susceptibility to, 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Aug 29, 2023	- -

Multiple endocrine neoplasia, type 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 620 of the RET protein (p.Cys620Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Hirschsprung disease and/or multiple endocrine neoplasia type 2 / medullary thyroid carcinoma (PMID: 7874109, 7881414, 9090527, 9681852, 10790203, 19336503, 21765987, 21986619). This variant is also known as the "Janus mutation". ClinVar contains an entry for this variant (Variation ID: 13915). 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, 9879991, 14715928). This variant disrupts the p.Cys620 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9230192, 9879991, 14715928). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2021	Variant summary: RET c.1858T>C (p.Cys620Arg) 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 was absent in 248804 control chromosomes (gnomAD). c.1858T>C has been reported in the literature in multiple individuals and families affected with Multiple Endocrine Neoplasia Type 2, Familial Medullary Thyroid Carcinoma and Hirschsprung Disease (e.g. Mulligan_1994, Hedayati_2011, Mathiesen_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that C620R-expressing cells are unable to migrate, differentiate, and be protected from apoptosis in response to GDNF but they possess ligand-independent rapid proliferation activity, providing an explanation for the ability of the variant to lead to both gain- and loss-of-function RET-associated diseases (Mograbi_2001, Arighi_2004). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Aganglionic megacolon;C4048306:Multiple endocrine neoplasia, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 03, 2018

The p.Cys620Arg variant in RET has been reported in over 30 individuals with cli nical features of multiple endocrine neoplasia type 2A (MEN2A; Mathiesen 2017, C huang 2016, Heilman 2016, Yeganeh 2015, Virtanen 2013, Frank-Raue 2011, Moore 20 09, Fialkowski 2008, Hofstra 2000, Schuffenecker 1994) and was absent from large population databases. The variant segregated with the disease in >50 affected r elatives (Mathiesen 2017, Vaclavikova 2012, Moore 2009, Fialkowski 2008, Hofstra 2000, Romeo 1998, Mulligan 1994). Multiple individuals with this variant were a lso determined to have Hirschsprung disease. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID#13915). In vitro functi onal studies provide some evidence that the p.Cys620Arg variant may impact prote in function (Arighi 2004, Chappuis-Flament 1998, Ito 1997). Mouse animal models have shown that this variant causes pre-cancerous lesions in the adrenal gland a nd C-cell hyperplasia in aged mice in heterozygotes, and kidney agenesis and int estinal aganglionosis in homozygotes (Yin 2007, Carniti 2006). In summary, this variant meets criteria to be classified as pathogenic for MEN2A in an autosomal dominant manner based upon segregation studies, absence from controls, and funct ional evidence. This variant is also associated with a risk of developing Hirsch sprung disease. Pathogenic variants in exon 10 of RET, especially affecting codo ns 618 and 620, often cause both MEN 2A and Hirschsprung disease (Eng 1996, Amer ican Thyroid Association Guidelines Task Force 2009). ACMG/AMP Criteria applied (Richards 2015): PS4, PP1_Strong, PM2, PM5, PS3_Moderate, PP3. -

Aganglionic megacolon Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Human Genomics Unit, Institute for molecular medicine Finland (FIMM)

Jan 01, 2013

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2022

The p.C620R pathogenic mutation (also known as c.1858T>C), located in coding exon 10 of the RET gene, results from a T to C substitution at nucleotide position 1858. The cysteine at codon 620 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been described in multiple families with RET-associated phenotypes including multiple endocrine neoplasia type 2A (MEN2A), familial medullary thyroid cancer (FMTC), and Hirschsprung disease (HSCR) (Schuffenecker I et al. Hum. Mol. Genet. 1994 Nov;3(11):1939-43; Pelet A et al. J. Med. Genet. 2005 Mar;42(3):e18; Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun;94(6):1938-44; Hedayati M et al. J Thyroid Res 2011; 264248; Vaclavikova E et al. Pediatr. Surg. Int. 2012 Feb;28(2):123-8). This mutation is located at codon 620, a well-described mutation hotspot site, and has been categorized by the American Thyroid Association as having moderate risk for MTC (formerly category B) and is associated with a pheochromocytoma risk of 13%–24% (Wells et al. Thyroid. 2015;25(6):567-610). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.037	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.95
MutPred		0.95		Gain of disorder (P = 0.01);.;Gain of disorder (P = 0.01);
MVP		1.0
MPC		0.93
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs77316810; hg19: chr10-43609102; COSMIC: COSV60691231;