NM_020975.6:c.1894G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS1

The NM_020975.6(RET):c.1894G>A(p.Glu632Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000454 in 1,607,222 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).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:2

Conservation

PhyloP100: 7.90

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 Likely_benign. Variant got -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.755

BP6

Variant 10-43114494-G-A is Benign according to our data. Variant chr10-43114494-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 24920.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=13}.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000433 (63/1455192) while in subpopulation SAS AF= 0.000383 (33/86256). AF 95% confidence interval is 0.00028. There are 0 homozygotes in gnomad4_exome. There are 36 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.1894G>A	p.Glu632Lys	missense_variant	Exon 11 of 20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 link	c.1894G>A	p.Glu632Lys	missense_variant	Exon 11 of 20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000971

AC:

AN:

247226

Hom.:

AF XY:

0.000112

AC XY:

AN XY:

134056

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000433

AC:

AN:

1455192

Hom.:

Cov.:

AF XY:

0.0000497

AC XY:

AN XY:

724220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

May 05, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17605401, 21479187, 16767674, 25440022, 34169762, 34570441, 31510104, 22648184, 30217742, 31159747, 14633923) -

Apr 12, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu632Lys variant in RET has been reported in 2 individuals with Hirschsprung's disease, 1 individual with medullary thyroid carcinoma, and 1 individual tested for a hereditary cancer panel (Carter 2011 PMID: 22648184, Romei 2015 PMID: 25440022, Tang 2018 PMID: 30217742, Tsaousis 2019 PMID: 31159747). It has also been identified in 0.05% (14/30612) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BP4. -

Nov 15, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RET c.1894G>A; p.Glu632Lys variant has been described in individuals affected with medullary thyroid cancer (MTC), Hirschsprung's disease, or pheochromocytoma (Carter 2012, Frank-Raue 2007, Han 2006, Romei 2015). It is reported as a variant of uncertain significance multiple times in ClinVar (Variation ID: 24920), and is observed in the general population at an overall frequency of 0.01% (24/247226 alleles) in the Genome Aggregation Database. The glutamic acid at codon 632 is moderately conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is tolerated. Due to limited information, the clinical significance of this variant cannot be determined with certainty. REFERENCES Carter TC et al. Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation. J Hum Genet. 2012 Aug;57(8):485-93. Frank-Raue K et al. Change in the spectrum of RET mutations diagnosed between 1994 and 2006. Clin Lab. 2007;53(5-6):273-82. Han ZY et al. Mutation screening of RET proto-oncogene in Chinese sporadic patients with pheochromocytoma. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2006 Jun;23(3):320-2. Romei C et al. Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer? Clin Endocrinol (Oxf). 2015 Jun;82(6):892-9. -

Jul 30, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RET: PM1 -

Multiple endocrine neoplasia type 2A

Uncertain:2Benign:1

Jun 10, 2023

Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 14, 2015

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 12, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Sep 09, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia type 2B

Uncertain:1

Dec 14, 2015

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Uncertain:1

Apr 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia, type 2

Uncertain:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 632 of the RET protein (p.Glu632Lys). This variant is present in population databases (rs377767407, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 17605401, 22648184, 25440022, 30217742, 31510104). ClinVar contains an entry for this variant (Variation ID: 24920). 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 tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;T;.

Eigen

Benign

0.18

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.4

M;.;M

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.1

N;N;N

REVEL

Uncertain

0.63

Sift

Benign

0.16

T;D;T

Sift4G

Benign

0.42

T;T;T

Polyphen

0.71

P;.;D

Vest4

0.76

MutPred

0.81

Gain of methylation at E632 (P = 0.0126);.;Gain of methylation at E632 (P = 0.0126);

MVP

0.87

MPC

0.23

ClinPred

0.12

GERP RS

3.6

Varity_R

0.15

gMVP

0.76

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

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