chr10-43119548-G-T

Position:

chr10-43119548-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1PM5PP3_ModeratePP5_Very_Strong

The NM_020975.6(RET):c.2410G>T(p.Val804Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,605,504 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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V804M) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 9.99

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PS1

Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-43119548-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

PP5

Variant 10-43119548-G-T is Pathogenic according to our data. Variant chr10-43119548-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 13946.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.2410G>T	p.Val804Leu	missense_variant	14/20	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.2410G>T	p.Val804Leu	missense_variant	14/20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152138

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

GnomAD3 exomes

AF:

0.00000430

AC:

AN:

232600

Hom.:

AF XY:

0.00

AC XY:

AN XY:

127712

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000525

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000138

AC:

AN:

1453366

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

722824

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000199

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

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:

0.00000756

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 15, 2023	The RET c.2410G>T; p.Val804Leu variant (rs79658334) has been reported in multiple individuals with familial medullary thyroid carcinoma (Lesueur 2005, Lombardo 2002, Patocs 2003) and multiple endocrine neoplasia type 2A (Learoyd 2005, Patocs 2003), segregating with affected individuals in the families (Learoyd 2005, Lombardo 2002, Patocs 2003). However, this variant was also found in some unaffected carriers in the pedigree, suggesting that it may have incomplete penetrance (Lombardo 2002, Patocs 2003). Functional characterization of the variant protein indicates autophosphorylation and activation of the kinase in the absence of growth factors, resulting in the increased phosphorylation of downstream targets and aberrant cell proliferation (Iwashita 1991, Pasini 1997). This variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 13946), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 804 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, the p.Val804Leu variant is considered to be pathogenic. References: Iwashita T et al. Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. Oncogene. 1991; 18(26):3919-22. Learoyd D et al. Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. Clin Endocrinol (Oxf). 2005; 63(6):636-41. Lesueur F et al. Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients. J Clin Endocrinol Metab. 2005; 90(6):3454-7. Lombardo F et al. Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804. J Clin Endocrinol Metab. 2002; 87(4):1674-80. Pasini A et al. Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain. Oncogene. 1997; 15(4):393-402. Patocs A et al. Segregation of the V804L mutation and S836S polymorphism of exon 14 of the RET gene in an extended kindred with familial medullary thyroid cancer. Clin Genet. 2003; 63(3):219-23. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2022	Published functional studies demonstrate a damaging effect: increased transforming activity and autophosphorylation (Carlomagno et al., 2004; Iwashita et al., 1999; Kodama et al., 2014; Pasini et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23811235, 7784092, 25637381, 23705946, 16507829, 26269449, 9067749, 23059849, 22162569, 15741265, 10235148, 9242375, 12694233, 20516206, 16532227, 27809725, 26678667, 16343097, 29590403, 31510104, 30624503, 33087929, 14633923, 26046350, 26247112, 11932300, 25349307, 15693160, 10445857, 15184865) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 29, 2021	PP1_strong, PP4, PP5, PM1, PM2, PM5, PS3_supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 30, 2017	- -

Multiple endocrine neoplasia, type 2

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 804 of the RET protein (p.Val804Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with medullary thyroid carcinoma and/or pheochromocytoma (PMID: 7784092, 10235148, 15741265, 16343097, 18058472, 18062802, 19469690, 21626080, 25810047, 26269449). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13946). 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: 9242375, 16507829, 26046350). This variant disrupts the p.Val804 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8797874, 9452077, 10876191). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 13, 2023	The c.2410G>T (p.Val804Leu) variant in the RET gene results in an amino acid change at residue 804 from Valine to Leucine. This variant has been observed in individuals with medullary thyroid carcinoma (PMID: 7784092, 11932300, 12694233, 15741265, 16343097, 18058472, 18062802, 19469690, 21626080). It has also been observed to segregate with disease in related individuals (PMID:15741265, 11932300, 12694233). However, this variant was also found in some unaffected carriers in the pedigree, suggesting that it may have incomplete penetrance (PMID:11932300, 12694233). Functional studies demonstrated that this variant had a gain-of-function effect on increased level of tyrosine phosphorylation compared to wildtype in one RET isoform and aberrant cell proliferation (PMID: 10445857, 9242375). This variant is rarely present in population databases (gnomAD). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (REVEL score ?0.7). A variant with distinct nucleotide change c.2410G>C, resulting in the same amino acid replacement p.Val804Leu, has been classified as pathogenic (ClinVar ID:38613). Another variant affecting the same amino acid, c.2410G>A (p.Val804Met), have also been classified as pathogenic (ClinVar ID:37102). Therefore, this variant c.2410G>T (p.Val804Leu) in RET is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2023	This missense variant replaces valine with leucine at codon 804 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant resulted in intermediate level of transforming activity on ex vivo transfected cells (PMID: 9242375, 10445857) and to confer resistance to select kinase inhibitors (PMID: 26046350, 26046350). This variant has been reported in dozens of heterozygous individuals affected with medullary thyroid cancer (PMID: 7784092, 10235148, 11932300, 12694233, 15741265, 20516206, 21626080) and one homozygous carrier affected with medullary thyroid cancer and pheochromocytoma (PMID: 15741265). This variant is also reported to segregate with disease in multiple families (PMID: 10235148, 11932300). This variant is reported to confer moderate risk for medullary thyroid cancer (PMID: 25810047). This variant has been identified in 1/232600 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Multiple endocrine neoplasia type 2A

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 18, 2023	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9242375]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20497437, 16343097, 11932300, 25810047]. -

Familial medullary thyroid carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2005

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2022

The p.V804L pathogenic mutation (also known as c.2410G>T), located in coding exon 14 of the RET gene, results from a G to T substitution at nucleotide position 2410. The valine at codon 804 is replaced by leucine, an amino acid with highly similar properties. This alteration occurs in the ATP binding pocket of the tyrosine-kinase domain of the RET receptor, and has been reported as a pathogenic mutation associated with both FMTC and MEN2A (Toledo SP et al. Clinics (Sao Paulo) 2006 Feb; 61(1):59-70; Raue F et al. Fam. Cancer 2010 Sep; 9(3):449-57). Additionally, this alteration was detected in conjunction with a second RET alteration, pVal648Ile, in another individual with features of MEN2A, including pheochromocytoma and medullary thyroid cancer (Verrienti A et al. Endocr Pract, 2015 Nov;21:1248-54). Functional studies demonstrate that p.V804L transfected cells exhibit an increase in the level of tyrosine phosphorylation compared to wildtype in one RET isoform, supporting its oncogenic potential (Pasini A et al. Oncogene 1997 Jul;15(4):393-402). In addition, expression studies demonstrate that p.V804L has a low transforming activity compared to other RET mutations. Transforming activity is associated with clinical phenotype; mutations with low transforming activity are associated with a milder MEN2/FMTC phenotype compared to mutations with high transforming activity that are associated with a more severe MEN2B phenotype (Iwashita T et al. Oncogene 1999 Jul;18(26):3919-22). The American Thyroid Association Guidelines Task Force has provided recommendations for individuals with RET gene mutations (Kloos et al. Thyroid. 2009 June; 19(6):565-612). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Multiple endocrine neoplasia;C1833921:Familial medullary thyroid carcinoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GenePathDx, GenePath diagnostics

Oct 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

D;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

-0.33

N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.0

N;N

REVEL

Pathogenic

0.71

Sift

Benign

0.031

D;D

Sift4G

Uncertain

0.027

D;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.90

Loss of methylation at K808 (P = 0.1007);Loss of methylation at K808 (P = 0.1007);

MVP

0.92

MPC

0.77

ClinPred

0.91

GERP RS

5.4

Varity_R

0.85

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

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