10-43114488-T-C

Position:

• chr10-43114488-T-C

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.1888T>C​(p.Cys630Arg) variant causes a missense change involving the alteration of a 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. C630F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.80

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 (HGNC:):

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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 10-43114488-T-C is Pathogenic according to our data. Variant chr10-43114488-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 24908.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.1888T>C	p.Cys630Arg	missense_variant	11/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1888T>C	p.Cys630Arg	missense_variant	11/20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

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	Dec 13, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 630 of the RET protein (p.Cys630Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with medullary thyroid carcinoma (MTC) (PMID: 14561794, 15523405, 16053382, 25440022). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24908). 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: 9879991). This variant disrupts the p.Cys630 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9223675, 17527003, 21054478, 26678667). 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	Nov 01, 2021	Variant summary: RET c.1888T>C (p.Cys630Arg) 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. The variant was absent in 246688 control chromosomes. c.1888T>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma (example, Machens_2004, Dourisboure_2005). 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 (example, Chappuis-Flament_1998). The most pronounced variant effect results in the constitutive activation of the RET receptor consistent with the established gain of function mechanism of disease. Two 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. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2024

The p.C630R variant (also known as c.1888T>C), located in coding exon 11 of the RET gene, results from a T to C substitution at nucleotide position 1888. The cysteine at codon 630 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been seen in multiple individuals and families diagnosed with medullary thyroid carcinoma (MTC), as well as in an individual with both an MTC and a parathyroid adenoma (Machens A et al. Surgery, 2004 Nov;136:1083-7; Elisei R et al. J. Clin. Endocrinol. Metab., 2007 Dec;92:4725-9; Romei C et al. Eur J Endocrinol, 2010 Aug;163:301-8; Martins-Costa MC et al. Arch Endocrinol Metab, 2018;62:623-635; Damavandi E et al. J Thyroid Res, 2021 Nov;2021:7250870). Additionally, it was shown to segregate with disease in a large kindred of more than 20 family members (Dourisboure RJ et al. Thyroid, 2005 Jul;15:668-71). This alteration was also shown to be an activating mutation which leads to a constitutive stimulation of the RET receptor by functional analysis (Chappuis-Flament S et al. Oncogene, 1998 Dec;17:2851-61). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Pathogenic	0.91
Sift	Benign	0.031	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.97
MutPred		0.90		Gain of disorder (P = 0.0188);.;Gain of disorder (P = 0.0188);
MVP		0.98
MPC		0.97
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.86
gMVP		0.97

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: rs377767404; hg19: chr10-43609936; COSMIC: COSV60690667;