rs79781594

Positions:

• chr10-43113649-G-A
• chr10-43113649-G-C
• chr10-43113649-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.1853G>A​(p.Cys618Tyr) variant causes a missense change. 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. C618R) 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:10
• Conservation: PhyloP100: 6.43

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 chr10-43113648-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 10-43113649-G-A is Pathogenic according to our data. Variant chr10-43113649-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 24901.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.1853G>A	p.Cys618Tyr	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.1853G>A	p.Cys618Tyr	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: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 618 of the RET protein (p.Cys618Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple endocrine neoplasia type 2A and familial medullary thyroid cancer (PMID: 8103403, 20516206, 21765987, 25628771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24901). 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: 7824936, 9174404, 9230192, 9879991). This variant disrupts the p.Cys618 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7915165, 9384613, 9498388, 9839497, 20979234, 22068382; Invitae). 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	Jan 07, 2021	Variant summary: RET c.1853G>A (p.Cys618Tyr) results in a non-conservative amino acid change located at a critical residue within 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 249080 control chromosomes. c.1853G>A has been widely reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma and subsequently cited by others (example, Donis-Keller_1993, Chiefari_1998, Beldjord_1995, Kimura_1995, Landsvater_1996). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in transforming activity of the RET proto-oncogene and reduced cell surface expression suggesting the potential to develop Hirschsprung's disease in addition to MEN 2A and FMTC (Ito_1997). Three 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 citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2023	Published functional studies demonstrate a damaging effect: increased transforming activity and homodimer formation (PMID: 9230192); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9879991, 9498388, 20979234, 23660264, 9839497, 8918855, 10490816, 7824936, 9174404, 19469690, 9384613, 7915165, 22068382, 26343386, 9699127, 7608256, 22747440, 8103403, 18063059, 20516206, 21765987, 11230481, 9761126, 31510104, 14633923, 29020875, 30666164, 26582918, 35053433, 37046785, 33827484, 32665702, 25628771, 9230192) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

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

- -

Multiple endocrine neoplasia type 2A Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

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

Mar 12, 2024

The p.C618Y pathogenic mutation (also known as c.1853G>A), located in coding exon 10 of the RET gene, results from a G to A substitution at nucleotide position 1853. The cysteine at codon 618 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in multiple individuals diagnosed with medullary thyroid carcinoma (MTC) and/or MEN2A (Frank-Raue K et al. Hum Mutat. 2011 Jan;32(1):51-8; Landsvater RM et al. Hum Genet. 1996 Jan;97(1):11-4; Quayle FJ et al. Surgery 2007 Dec;142(6):800-5; discussion 805.e1; Zhao JQ et al. Hered Cancer Clin Pract. 2015 Jan;13(1):5). In addition, several other missense alterations that change the cysteine at codon 618 have been reported in the literature as disease-causing mutations (Landsvater RM et al. Hum Genet. 1996 Jan;97(1):11-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). The American Thyroid Association categorizes alterations to the C618 residue, including p.C618Y, in the B-level risk group and has made mutation specific guidelines available (Kloos RT et al. Thyroid 2009 Jun; 19(6):565-612). 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	0.95
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Pathogenic	0.61	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	0.65	T
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.85	P;.;P
Vest4		0.97
MutPred		0.92		Loss of methylation at K617 (P = 0.0145);.;Loss of methylation at K617 (P = 0.0145);
MVP		0.98
MPC		0.95
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.92
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: rs79781594; hg19: chr10-43609097; COSMIC: COSV60703802;