10-43113622-G-C

Variant names:

• chr10-43113622-G-C
• rs77939446
• NM_020975.6:c.1826G>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.1826G>C​(p.Cys609Ser) 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. C609G) 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:4
• Conservation: PhyloP100: 8.13

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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 10-43113622-G-C is Pathogenic according to our data. Variant chr10-43113622-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1372611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.1826G>C	p.Cys609Ser	missense_variant	Exon 10 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1826G>C	p.Cys609Ser	missense_variant	Exon 10 of 20	5	NM_020975.6	ENSP00000347942.3

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

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 17, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C609S pathogenic mutation (also known as c.1826G>C), located in coding exon 10 of the RET gene, results from a G to C substitution at nucleotide position 1826. The cysteine at codon 609 is replaced by serine, an amino acid with dissimilar properties. Codon 609 of the RET gene is a known hotspot for MEN2 mutations with well documented phenotype/genotype correlations, and The American Thyroid Association Guidelines Task Force has provided recommendations (Wells SA, Thyroid 2015 Jun; 25(6):567-610.). One study of 65 unrelated medullary thyroid cancer (MTC) families reported the p.C609S mutation in a family affected by MTC and the presence of pheochromocytomas (Klein et al. Journal of Endocrinology (2001) 170, 661–666). Codon 609 mutations have been well documented to lead to increased risks for MTC, parathyroid disease, pheochromocytomas, and Hirschprung disease (Mian et al. Familial Cancer (2009) 8:379–382, Mian C, Clinics (Sao Paulo) 2012 ; 67 Suppl 1:33-6). Based on the available evidence, p.C609S is classified as a pathogenic mutation. -

Feb 03, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Multiple endocrine neoplasia type 2A Pathogenic:1

Apr 06, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16343103]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16343103, 19475497, 16865647, 18976013, 25810047]. -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Apr 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 609 of the RET protein (p.Cys609Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple endocrine neoplasia type 2A (PMID: 11524247, 16343103, 22584703). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1372611). 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: 16343103). This variant disrupts the p.Cys609 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19472011, 22734615, 24617864). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.7	M;.;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.8	D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.94		Gain of glycosylation at C609 (P = 0.0183);.;Gain of glycosylation at C609 (P = 0.0183);
MVP		0.99
MPC		0.84
ClinPred		1.0	D
GERP RS		4.9
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: rs77939446; hg19: chr10-43609070;