10-43113654-T-G

Position:

• chr10-43113654-T-G

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.1858T>G​(p.Cys620Gly) 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. 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:7
• Conservation: PhyloP100: 6.52

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 ClinVar as [Pathogenic]. Clinvar id is 13928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 10-43113654-T-G is Pathogenic according to our data. Variant chr10-43113654-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 24905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1858T>G	p.Cys620Gly	missense_variant	10/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1858T>G	p.Cys620Gly	missense_variant	10/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This missense variant replaces cysteine with glycine at codon 620 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least a dozen cases of sporadic and familial medullary thyroid cancer with or without pheochromocytoma and hyperparathyroidism (PMID: 9223675, 11502806, 14718397, 20516206, 20979234, 25694125, 28946813, 29579362, 35884466; DOI: 10.1210/jendso/bvab048.2029). Three other missense mutations at codon 620 are considered a moderate risk for MTC by the American Thyroid Association and approximately 10% to 20% of carriers are affected with pheochromocytoma and hyperparathyroidism (PMID: 25810047). This codon, cysteine 620, is considered a RET mutational hotspot observed in MEN2 disease and sporadic medullary thyroid carcinoma (PMID: 33603219). Five other protein changes at this codon from six different single-nucleotide substitutions have been reported as disease-causing in ClinVar (variation ID: 13915, 13916, 13928, 13934, 13943, 38602). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 26, 2022	ClinVar contains an entry for this variant (Variation ID: 24905). For these reasons, this variant has been classified as Pathogenic. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with Hirschsprung disease, medullary thyroid cancer, and/or pheochromocytoma (PMID: 20516206, 20979234, 25694125, 30763276). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 620 of the RET protein (p.Cys620Gly). -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2016

- -

Aganglionic megacolon;C4048306:Multiple endocrine neoplasia, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 24, 2017

The p.Cys620Gly variant in RET has been reported in at least 10 probands with R ET-associated disorders (diagnoses included medullary thyroid carcinoma (MTC), m ultiple endocrine neoplasia type 2A (MEN2A), and/or Hirschsprung disease) and se gregated with disease in at least 4 individuals from at least family (Kitamura 1 997, Niccoli-Sire 2001, Kruckeberg 2004, Frank-Raue 2011). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID# 24905) a nd was absent from large population studies. Additionally, other amino acid cha nges at this position have been reported in patients with MEN2A, and variants at cysteine residues in exon 10 or 11 of RET account for the majority of familial MTC and MEN2A cases (Hansford 2000, Kruckeberg 2004, Coyle 2014). Computational prediction tools and conservation analysis also suggest that the p.Cys620Gly var iant may impact the protein. In summary, this variant meets criteria to be class ified as pathogenic for MEN2A in an autosomal dominant manner based on presence in multiple affected individuals, segregation studies, absence from the general population, presence in a mutational hotspot and computational evidence. ACMG/AM P Criteria applied: PS4, PM1, PM2, PP3, PP1_supporting (Richards 2015). -

Multiple endocrine neoplasia type 2A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Apr 10, 2018

This c.1858T>G (p.Cys620Gly) variant in the RET gene has been reported in multiple unrelated individuals with medullary thyroid carcinoma and Hurschsprung disease (PMID: 8918855, 9223675, 25694125, 20979234, 11502806) and is extremely rare in the general population. Other reports have also observed different changes at the same amino acid in patients with medullary thyroid carcinoma (PMID:7874109, 7849720). This c.1858T>G (p.Cys620Gly) variant in the RET gene is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30624503, 20516206, 25694125, 12686527, 9067749, 15982921, 24972642, 11502806, 9223675, 8918855, 14718397, 30763276, 31447099, 18058472, 20979234, 14633923) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2022

The p.C620G pathogenic mutation (also known as c.1858T>G), located in coding exon 10 of the RET gene, results from a T to G substitution at nucleotide position 1858. The cysteine at codon 620 is replaced by glycine, an amino acid with highly dissimilar properties. This mutation has been described in multiple families with RET-associated phenotypes (Eng C et al. Hum. Mutat. 1997; 9(2):97-109.; Raghavan R et al. Multiple endocrine neoplasia type 2A in a large family with a C620G mutation of the RET proto-oncogene: diagnostic, treatment, and ethical challenges [abstract]. In: Society for Endocrinology BES; 2014 March 24-27; Liverpool, UK; Yeganeh MZ et al. Tumour Biol. 2015 Jul; 36(7):5225-31).This mutation is located in codon 620, which encodes part of the extracellular cysteine rich domain and is a well-described mutation hotspot site. Mutations at this codon have 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). 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 interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.94	D;D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Pathogenic	0.88	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	0.51	T
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.98
MutPred		0.95		Gain of disorder (P = 0.0087);.;Gain of disorder (P = 0.0087);
MVP		1.0
MPC		0.72
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.95
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: rs77316810; hg19: chr10-43609102;