chr10-43113655-G-T

Position:

• chr10-43113655-G-T

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.1859G>T​(p.Cys620Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C620R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 8.13

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 (HGNC:):

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 chr10-43113654-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 10-43113655-G-T is Pathogenic according to our data. Variant chr10-43113655-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 13928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43113655-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.1859G>T	p.Cys620Phe	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.1859G>T	p.Cys620Phe	missense_variant	10/20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 20, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 13, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2022	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: 8909322, 19443294, 33340421, 19826964, 14715928, 16705552, 20979234, 21765987, 7916559, 25694125, 7874109, 18976013, 25810047, 26033033, 31510104, 20516206, 14633923, 18063059, 20664475, 7915165, 19469690, Khalfa2021[abstract]) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Multiple endocrine neoplasia type 2A Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 08, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 10, 2022	The p.C620F pathogenic mutation (also known as c.1859G>T), located in coding exon 10 of the RET gene, results from a G to T substitution at nucleotide position 1859. The cysteine at codon 620 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple families who satisfy diagnostic criteria for multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid cancer (FMTC) (Schuffenecker I et al. Hum Molec Genet. 1994;3(11):1939-1943, Hedayati M et al. J Thyroid Res. 2011;2011:264248, Frank-Raue K et al. Hum Mutat. 2011 Jan;32(1):51-8), Vaclavikova E, Endocrine 2009 Dec; 36(3):419-24, Dvorakova S, Exp. Clin. Endocrinol. Diabetes 2006 Apr; 114(4):192-6). This mutation is located in codon 620 of the RET gene, a well-described mutation hotspot, and has been categorized by the American Thyroid Association as having moderate risk for MTC and is associated with a pheochromocytoma incidence rate of 13%–24% (Wells, et al. Thyroid. 2015;25(6):567-610). Based on the available evidence, p.C620F is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jul 14, 2021	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 05, 2018

The RET c.1859G>T; p.Cys620Phe variant has been described in the literature in individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (FMTC) (American Thyroid Association Guidelines Task Force 2009, Hedayati 2011, Romei 2011, Wells 1994). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13928), but it is absent from general population-based databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 620 is highly conserved across species, it occurs in the cysteine-rich extracellular RET domain and computational programs (PolyPhen2, SIFT) predict this variant to be deleterious. Additionally, other amino acid substitutions at this codon (Ser, Arg, Gly, Trp, and Tyr) have been reported in individuals with MEN2 and FMTC and are considered pathogenic (American Thyroid Association Guidelines Task Force 2009, Frank-Raue 2011, Romei 2011). Based on available evidence, the p.Cys620Phe variant is considered to be pathogenic. References: American Thyroid Association Guidelines Task Force et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19(6):565-612. 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;2011:264248. 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. Romei C et al. RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin Endocrinol (Oxf). 2011 Feb;74(2):241-7. Wells SA Jr et al. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg. 1994 Sep;220(3):237-4. -

Multiple endocrine neoplasia type 2B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

May 08, 2016

- -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 620 of the RET protein (p.Cys620Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid cancer and pheochromocytoma (PMID: 7915165, 8909322, 16705552, 19443294, 20979234). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13928). 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. 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: 7874109, 9012462, 9230192, 9879991, 20979234). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.7	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.97
MutPred		0.94		Gain of loop (P = 0.0851);.;Gain of loop (P = 0.0851);
MVP		0.99
MPC		0.76
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
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: rs77503355; hg19: chr10-43609103;