rs377767395

Positions:

• chr10-43113613-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_020975.6(RET):​c.1817A>G​(p.Tyr606Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y606H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.72

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_020975.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866
• PP5: Variant 10-43113613-A-G is Pathogenic according to our data. Variant chr10-43113613-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 24892.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1817A>G	p.Tyr606Cys	missense_variant	10/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1817A>G	p.Tyr606Cys	missense_variant	10/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460850 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726638

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2019

The p.Y606C variant (also known as c.1817A>G), located in coding exon 10 of the RET gene, results from an A to G substitution at nucleotide position 1817. The tyrosine at codon 606 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with a diagnosis of medullary thyroid cancer (MTC) (Ahmed SA et al. J Mol Diagn 2005 May;7(2):283-8, Ercolino T et al. Clin. Endocrinol. (Oxf). 2008 Aug;69(2):253-8, Ambry internal data). Functional studies have demonstrated that this alteration leads to increased autophosphorylation and dimerization of the RET protein, and increased phosphorylation of downstream RET targets, suggesting that it is an activating mutation (Ercolino T et al. Clin. Endocrinol. (Oxf). 2008 Aug;69(2):253-8). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Multiple endocrine neoplasia, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 25, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects RET function (PMID: 18248647). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 24892). This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 15858153, 18248647, 26254625). 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 tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 606 of the RET protein (p.Tyr606Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	0.70	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.054	T;D;T
Sift4G	Benign	0.12	T;D;T
Polyphen		0.99	D;.;D
Vest4		0.47
MutPred		0.76		Gain of disorder (P = 0.0126);.;Gain of disorder (P = 0.0126);
MVP		0.93
MPC		0.65
ClinPred		0.90	D
GERP RS		3.8
Varity_R		0.56
gMVP		0.89

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: rs377767395; hg19: chr10-43609061;