Variant 10-43114507-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_020975.6(RET):c.1907C>T(p.Thr636Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,456,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 3.24

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:

RET (HGNC:):

RET links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3968686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6 linkuse as main transcript	c.1907C>T	p.Thr636Met	missense_variant	11/20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.1907C>T	p.Thr636Met	missense_variant	11/20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

247916

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1456188

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724648

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000209

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000315

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hirschsprung disease, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 14, 2024

- -

Multiple endocrine neoplasia type 2A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Jul 02, 2018

- -

Multiple endocrine neoplasia, type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 636 of the RET protein (p.Thr636Met). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 25725622). ClinVar contains an entry for this variant (Variation ID: 405553). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects RET function (PMID: 25725622). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest a damaging effect: increased cell growth, migration, and proliferation, as well as decreased contact inhibition compared to wildtype; however, these effects were reportedly milder than the p.C634R positive control (PMID: 25725622); This variant is associated with the following publications: (PMID: 14633923, 30755392, 26319365, 30446652, 26678667, 27311873, 25725622, 35264596) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2023

The p.T636M variant (also known as c.1907C>T), located in coding exon 11 of the RET gene, results from a C to T substitution at nucleotide position 1907. The threonine at codon 636 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in a woman diagnosed with sporadic medullary thyroid cancer at age 78 years of age. Functional assays measuring cell growth and proliferation, contact inhibition, and cell migration showed levels somewhat higher than wild-type, which the authors described as low-grade transforming potential (Silva AL et al. Endocrine. 2015 Jun;49(2):366-72). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

RET-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2023

The RET c.1907C>T variant is predicted to result in the amino acid substitution p.Thr636Met. This variant has been reported in an individual with thyroid cancer (Silva et al. 2015. PubMed ID: 25725622). This variant has been reported in a presumed unaffected parent from an exome trio analysis (Table S2, Ji et al. 2019. PubMed ID: 30755392). In vitro experimental studies suggest this variant may impact protein function (Silva et al. 2015. PubMed ID: 25725622). This variant is reported in 3 of ~248,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/10-43609955-C-T) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/405553/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;T;.

Eigen

Benign

0.0073

Eigen_PC

Benign

0.097

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.40

T;T;T

MetaSVM

Uncertain

0.77

MutationAssessor

Benign

1.8

L;.;L

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.1

N;N;N

REVEL

Pathogenic

0.77

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.37

B;.;P

Vest4

0.73

MutPred

0.41

Loss of catalytic residue at T636 (P = 0.0231);.;Loss of catalytic residue at T636 (P = 0.0231);

MVP

0.69

MPC

0.26

ClinPred

0.31

GERP RS

3.5

Varity_R

0.090

gMVP

0.77

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