chr10-43113648-T-A

Position:

chr10-43113648-T-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM2PM5PP3_StrongPP5_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 Lovd. 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.95

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PS1

Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

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, 0.987

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	Protein	UniProt
RET	NM_020975.6 linkuse as main transcript	c.1852T>A	p.Cys618Ser	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 linkuse as main transcript	c.1852T>A	p.Cys618Ser	missense_variant	10/20	5	NM_020975.6	ENSP00000347942	P4	P07949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249068

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134912

show subpopulations

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.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia type 2A

Pathogenic:2

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. -
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	- -

Multiple endocrine neoplasia, type 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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

May 20, 2024

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. This alteration 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). This alteration had been identified in two families in the literature presenting with a clinical diagnosis of MEN2A/FMTC and Hirschsprung disease (Decker RA et al. Hum Mol Genet, 1998 Jan;7:129-34). This mutation has been classified as conferring "moderate risk" for MTC by the American Thyroid Association (Wells SA et al. Thyroid 2015 Jun; 25(6):567-610). 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 pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. -

RET-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

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

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

D;D;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.75

T;T;T

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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