rs76262710

chr10-43113648-T-Achr10-43113648-T-Cchr10-43113648-T-G

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):c.1852T>A(p.Cys618Ser) 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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C618F) 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:8
• Conservation: PhyloP100: 4.95

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 26 ACMG points.

• PS1: Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 13914
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_020975.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43113649-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 24902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 10-43113648-T-A is Pathogenic according to our data. Variant chr10-43113648-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 38601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43113648-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1852T>A	p.Cys618Ser	missense_variant	10/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1852T>A	p.Cys618Ser	missense_variant	10/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249068 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134912

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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 2A Pathogenic:2

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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2023	Variant summary: RET c.1852T>A (p.Cys618Ser) 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. Other variants at the same codon (p.Cys618Arg, p.Cys618Gly, p.Cys618Phe) have been reported in association with Multiple Endocrine Neoplasia and this codon is considered a well known hotspot suggestive of the critical relevance of this residue to RET protein function. The variant allele was found at a frequency of 4e-06 in 249068 control chromosomes. c.1852T>A has been reported in the literature in multiple individuals affected with features of Multiple Endocrine Neoplasia Type 2A (example, Decker_1998, Siegelman_1997, Biaugrand_1994, Borst_1995, Ahmed_2005). These data indicate that the variant is very likely to be associated with disease. The American Thyroid Association reports this variant as associated with an increased risk for medullary thyroid cancer and pheochromocytoma (Kloos_2009). The following publications have been ascertained in the context of this evaluation (PMID: 15858153, 7849720, 7716719, 9498388, 9230192, 9068588, 9824583, 16849421, 17590169, 17605401, 19469690). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Multiple endocrine neoplasia, type 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 618 of the RET protein (p.Cys618Ser). This variant is present in population databases (rs76262710, gnomAD 0.0009%). A different variant (c.1853G>C) giving rise to the same protein effect has been determined to be pathogenic (PMID: 7849720, 7915165, 9384613, 9498388, 9839497, 15858153, 20119574, 20979234, 21765987, 22068382). This suggests that this variant is also likely to be causative of disease. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38601). 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: 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). 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	All of Us Research Program, National Institutes of Health	Nov 13, 2023	This c.1852T>A (p.Cys618Ser) variant of the RET gene has been reported in multiple individuals and several families affected with familial medullary thyroid cancer (FMTC) and multiple endocrine neoplasia type 2A (PMID: 7849720, 20119574, 22068382, 21765987, 15858153, 20979234). It has been reported to segregate with the disease in families (PMID: 20119574, 22068382, 15858153, 20979234). This variant is rare (1/249068) in the general population database (gnomAD). This variant is predicted to be deleterious by REVEL. Experimental studies have shown that several amino acid substitutions at this position, including p.Cys618Ser, have transforming activity in cell culture and result in intracellular retention and reduced cell surface expression of RET (PMID: 9230192). Another variant, c.1853G>C (p.Cys618Ser) with a different nucleotide change but resulting in the same protein change observed here, has been reported in individuals and families affected with medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2A (PMID: 7915165, 9498388,9839497, 9384613, 20979234). Therefore, the c.1852T>A (p.Cys618Ser) variant of RET gene is classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 03, 2022	PP1_strong, PP3, PP4, PM1, PM2, PM5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2021	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: 20979234, 9384613, 7849720, 22199277, 20119574, 21765987, 8557249, 12734540, 18063059, 18062802, 15858153, 22068382, 9003111, 15588376, 26254625, 9699127, 27277749, 20516206, 9498388, 26758973, 7716719, 7874109, 8849576, 31471357, 31510104, 14633923) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2018

The p.C618S pathogenic mutation (also known as c.1852T>A), located in coding exon 10 of the RET gene, results from a T to A substitution at nucleotide position 1852. The cysteine at codon 618 is replaced by serine, an amino acid with dissimilar properties. The American Thyroid Association reports that this alteration is associated with an increased risk for medullary thyroid cancer and pheochromocytoma (Kloos RT et al. Thyroid. 2009 Jun;19(6):565-612; Wells SA et al. Thyroid 2015 Jun;25(6):567-610). In addition, it has been identified in multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid carcinoma (FMTC) patients and families (Qi XP et al. Fam. Cancer. 2012 Mar;11(1):131-6; Jung J et al. Korean Med. Sci. 2010 Feb;25(2):226-9; Margraf R et al. Hum Mutat. 2009 Apr;30(4):548-56; Schuffenecker I et al. Hum Mol Genet. 1994 Nov;3(11):1939-43). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

RET-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2023

The RET c.1852T>A variant is predicted to result in the amino acid substitution p.Cys618Ser. This variant was reported in patients with multiple endocrine dysplasia type 2A and familial medullary thyroid carcinoma (Blaugrund et al. 1994. PubMed ID: 7849720; Jung et al. 2010. PubMed ID: 20119574; Romei et al. 2010. PubMed ID: 20516206; Hedayati et al. 2011. PubMed ID: 21765987; Qi et al. 2012. PubMed ID: 22068382). Of note, several missense variants affecting the same amino acid (p.Cys618Arg, p.Cys618Gly, p.Cys618Tyr, p.Cys618Phe) have also been reported to be pathogenic for multiple endocrine dysplasia type 2A and familial medullary thyroid cancer (HGMD database; Romei et al. 2010. PubMed ID: 20516206). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-43609096-T-A) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38601/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Pathogenic	0.80	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	0.56	T
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.020	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.96	D;.;D
Vest4		0.98
MutPred		0.93		Gain of disorder (P = 0.0037);.;Gain of disorder (P = 0.0037);
MVP		0.99
MPC		0.37
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.89
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: rs76262710; hg19: chr10-43609096;