rs79890926

Positions:

• chr10-43113656-C-G
• chr10-43113656-C-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.1860C>G​(p.Cys620Trp) variant causes a missense change involving the alteration of a non-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:4
• Conservation: PhyloP100: -0.193

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 10-43113656-C-G is Pathogenic according to our data. Variant chr10-43113656-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 13934.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.1860C>G	p.Cys620Trp	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.1860C>G	p.Cys620Trp	missense_variant	10/20	5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA, WITH HIRSCHSPRUNG DISEASE Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 28, 2017

- -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 12, 2020

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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individuals with MEN2A, medullary thyroid cancer and Hirschsprung disease (PMID: 9146685, 9384613, 21542403, 19853744, 20979234, 20152359). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13934). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tryptophan at codon 620 of the RET protein (p.Cys620Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant disrupts the p.Cys620 amino acid residue in RET. Other variants that disrupt this residue have been determined to be pathogenic (PMID: 20979234, 15472167, 9012462, 8909322, 16705552, 19443294, 20979234, 7915165, 10777380, 14517954, 11471675, 9230192). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); 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: 17270543, 21542403, 14718397, 19853744, 9384613, 22811860, Margraf[CaseRpt]2012, 14633923, 9146685, 20979234, 20152359, 9068588) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2022

The p.C620W pathogenic mutation (also known as c.1860C>G), located in coding exon 10 of the RET gene, results from a C to G substitution at nucleotide position 1860. The cysteine at codon 620 is replaced by tryptophan, an amino acid with highly dissimilar properties. This mutation has previously been reported in multiple families affected with MEN2A, Hirschsprung disease and/or medullary thyroid carcinoma (MTC) (Decker RA et al. Hum. Mol. Genet., 1998 Jan;7:129-34; Heshmati HM et al. Mayo Clin. Proc., 1997 May;72:430-6; Frank-Raue K et al. Hum. Mutat., 2011 Jan;32:51-8). In addition, codon 620 is a well-described mutation hotspot and several other mutations at this same codon have been categorized by the American Thyroid Association as having moderate risk for MTC (Wells, et al. Thyroid. 2015;25(6):567-610). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.97
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.95	D;D;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.0	D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.96
MutPred		0.92		Loss of disorder (P = 0.0519);.;Loss of disorder (P = 0.0519);
MVP		0.99
MPC		0.90
ClinPred		0.99	D
GERP RS		-6.2
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79890926; hg19: chr10-43609104;