chr10-43114596-A-G

Position:

chr10-43114596-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5PP3PP5_Very_Strong

The NM_020975.6(RET):c.1996A>G(p.Lys666Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,078 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K666M) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10B:1

Conservation

PhyloP100: 7.33

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-43114597-A-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

PP5

Variant 10-43114596-A-G is Pathogenic according to our data. Variant chr10-43114596-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24931.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 linkuse as main transcript	c.1996A>G	p.Lys666Glu	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 linkuse as main transcript	c.1996A>G	p.Lys666Glu	missense_variant	11/20	5	NM_020975.6	ENSP00000347942	P4	P07949-1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460828

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726732

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151250

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73784

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hirschsprung disease, susceptibility to, 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 17, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 28, 2021	- -

Multiple endocrine neoplasia, type 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 27, 2024	The c.1996A>G (p.Lys666Glu) variant in the RET gene is located on the exon 11 and is predicted to replace lysine with glutamine at codon 666 of the receptor tyrosine kinase RET. This variant has been reported in individuals with multiple endocrine neoplasia or medullary thyroid carcinoma with incomplete penetrance (PMID:15858153, 32375120, 25440022, 30927507). Functional studies showed increased kinase and transforming activities in transfected HEK293 cells (PMID: 21690267). ClinVar contains an entry for this variant (ID: 24931). Another missense variant affecting the same codon, c.1998G>C (p.Lys666Asn), has also been reported to be pathogenic/likely pathogenic (ClinVar ID: 230926). This variant has not been observed in the general population according to gnomAD database. Based on this evidence, the c.1996A>G (p.Lys666Glu) variant in the RET gene is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 666 of the RET protein (p.Lys666Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid cancer and pheochromocytoma (PMID: 15858153, 21690267, 30927507). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24931). 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: 21690267). This variant disrupts the p.Lys666 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20103606, 26269449, 27673361). 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:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2024	Categorized as a moderate risk allele for aggressive medullary thyroid carcinoma by the American Thyroid Association (PMID: 25810047); Published functional studies demonstrate increased transforming activity and ERK phosphorylation (PMID: 21690267); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 20103606, 27673361, 29590403, 29284153, 24699901, 25440022, 26732158, 29408964, 27809725, 26678667, 28740527, 15858153, 31510104, 32375120, 30927507, 37900832, 14633923, 32376047, 38339246, 26580448, 33340421, 37835559, 21690267, 25810047) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 03, 2022	PP1, PP5, PM2, PS3, PS4_moderate -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 28, 2023	The p.K666E pathogenic mutation (also known as c.1996A>G), located in coding exon 11 of the RET gene, results from an A to G substitution at nucleotide position 1996. The lysine at codon 666 is replaced by glutamic acid, an amino acid with similar properties. This mutation has been identified in three unrelated families with medullary thyroid cancer. In one family, 12 individuals were tested, and the mutation was observed to segregate with disease in 6/6 affected individuals (Ahmed SA et al. J Mol Diagn 2005;7:283-8). In an in vitro focus formation assay, the mutant protein demonstrated transforming activity and oncogenic potential at levels higher than wild type, but lower than the well-described pathogenic p.C634R mutation (Borrello MG et al. Endocr. Relat. Cancer 2011; 18:519-27). Another pathogenic alteration at this codon (p.K666N) has been described in a female with sporadic medullary thyroid cancer and was also observed to have increased oncogenic potential compared to the wild type (Muzza M et al. Eur J Endocrinol. 2010 Apr;162(4):771-7). 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 pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. -

Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 16, 2022

- -

Multiple endocrine neoplasia type 2A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 05, 2024

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15858153, 30927507, 21690267, 25810047]. Functional studies indicate this variant impacts protein function [PMID: 21690267]. -

Medullary thyroid carcinoma

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.6

N;N

REVEL

Pathogenic

0.78

Sift

Uncertain

0.015

D;D

Sift4G

Benign

0.089

T;T

Polyphen

0.99

D;D

Vest4

0.79

MVP

0.93

MPC

0.79

ClinPred

0.96

GERP RS

4.8

Varity_R

0.33

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over