rs77503355

Positions:

• chr10-43113655-G-A
• chr10-43113655-G-C
• 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>A​(p.Cys620Tyr) 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. C620F) 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]

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 10-43113655-G-A is Pathogenic according to our data. Variant chr10-43113655-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.1859G>A	p.Cys620Tyr	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>A	p.Cys620Tyr	missense_variant	10/20	5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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	Dec 04, 2020	The RET c.1859G>A; p.Cys620Tyr variant is published in the medical literature in individuals affected with multiple endocrine neoplasia type 2A (MEN2A) or MEN2A-associated cancers (Donis-Keller 1993, Frank-Raue 2011, Orgiana 2004). Additionally, other amino acid substitutions at this codon (Arg, Phe, and Ser) are described as causative for MEN2A, though missense variants at this codon often exhibit incomplete penetrance (Wells 2015). The p.Cys620Tyr variant is reported as pathogenic by multiple laboratories in the ClinVar database (Variation ID: 13916), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 620 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Considering available information, the p.Cys620Tyr variant is considered to be pathogenic. References: 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. 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. Orgiana G et al. A new germline RET mutation apparently devoid of transforming activity serendipitously discovered in a patient with atrophic autoimmune thyroiditis and primary ovarian failure. J Clin Endocrinol Metab. 2004 Oct;89(10):4810-6. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 13, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2024	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: 18062802, 21309721, 9174404, 16158949, 18248647, 20979234, 9067749, 8103403, 12563086, 16411177, 21995290, 22865907, 8733882, 28698976, 26556299, 9681515, 31510104, 32408902, 35668420, 25810047, 9146685, 19336503, 7874109, 16868135, 9230192, 8797874, 8654369, 19826964, 24805091, 18063059, 7849720, 18206480, 16322339, 34092334, 9384613, 9820617, 15472167, 38753300, 14633923, 20065189, 29656518) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 07, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Over 90% of MEN2A and FMTC families have missense variants in one of six conserved cysteine residues at codons 609, 611, 618, 620, 630 or 634 in the extracellular cysteine-rich region (PMID 19443294). This variant is defined by the American Thyroid Association as being of moderate risk for developing MTC (PMID: 19469690, 25810047). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant activates RET protein kinase transforming capability, thereby inducing the protein's oncogenic activation (PMID 9230192, 18248647, 15472167, 9012462). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. -

Multiple endocrine neoplasia type 2A Pathogenic:3

Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 13, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 04, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Apr 30, 2009	- -

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

- -

Multiple endocrine neoplasia, type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Aganglionic megacolon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Apr 30, 2009

- -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 620 of the RET protein (p.Cys620Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid carcinoma (MTC) and pheochromocytoma (PMID: 8797874, 9820617, 16322339, 16868135, 18062802, 18063059, 20979234, 26556299). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13916). 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 tolerated. Experimental studies have shown that this missense change affects RET function (PMID: 9012462, 15472167). 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: 7849720, 7874109, 9146685, 9384613, 18206480, 19336503, 19826964, 24805091). 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. -

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 20, 2022

The c.1859G>A (p.C620Y) alteration is located in exon 10 (coding exon 10) of the RET gene. This alteration results from a G to A substitution at nucleotide position 1859, causing the cysteine (C) at amino acid position 620 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This pathogenic mutation has been well described in numerous individuals with familial medullary thyroid cancer (FMTC) (Donis-Keller, 1993; Schuffenecker, 1994; Fink, 1996; Frank-Raue, 2011; Schrader, 2016) and has also been described in a patient with Hirschsprung disease (Frank-Raue, 2011). Furthermore, codon 620 is a well-described mutation hotspot with numerous pathogenic alterations reported at this position (Kloos, 2009; Wells, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.98
MutPred		0.93		Gain of loop (P = 0.0851);.;Gain of loop (P = 0.0851);
MVP		0.99
MPC		0.41
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.93
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;