10-43119548-G-C

Position:

chr10-43119548-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_020975.6(RET):c.2410G>C(p.Val804Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,366 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. V804M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a domain Protein kinase (size 292) in uniprot entity RET_HUMAN there are 21 pathogenic changes around while only 2 benign (91%) in NM_020975.6

PM2

Very rare variant in population databases, with high coverage;

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, 0.973

PP5

Variant 10-43119548-G-C is Pathogenic according to our data. Variant chr10-43119548-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119548-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6 linkuse as main transcript	c.2410G>C	p.Val804Leu	missense_variant	14/20	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.2410G>C	p.Val804Leu	missense_variant	14/20	5	NM_020975.6	ENSP00000347942	P4	P07949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1453366

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722824

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	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). This variant has been reported in three individuals affected with endocrine neoplasias and two related individuals affected with medullary thyroid cancer (PMID: 11114642, 28946813). Different variants occurring at the same codon, c.2410G>A (p.Val804Met) and c.2410G>T (p.Val804Leu), are well-documented pathogenic mutations (ClinVar variation ID: 37102, 13946), indicating that valine at this position is important for RET protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 17, 2023	For these reasons, this variant has been classified as Pathogenic. 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: 7784092, 10235148, 15741265, 16343097, 18058472, 26269449). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 38613). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2 (PMID: 7784092, 10235148, 14718397, 15741265, 16343097, 18058472, 26269449). This variant is not present in population databases (gnomAD no frequency). 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). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2023	Published functional studies demonstrate a damaging effect: increased transforming activity and autophosphorylation ability (Carlomagno et al., 2004; Iwashita et al., 1999; 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: 9879991, 10445857, 16532227, 11114642, 14718397, 9384613, 26247112, 20516206, 16865647, 10235148, 23705946, 18322301, 9242375, 15741265, 20497437, 16343097, 26269449, 25810047, 7784092, 18058472, 14633923, 11932300, 15184865, 30763276) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -

MEN2 phenotype: Unclassified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 06, 2023

Variant summary: RET c.2410G>C (p.Val804Leu) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 232600 control chromosomes (gnomAD). c.2410G>C has been reported in the literature in multiple individuals affected with Medullary Thyroid Carcinoma and Multiple Endocrine Neoplasia (example: Lombardo_2002, Paszko_2007, and Maciel_2019). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Multiple endocrine neoplasia type 2A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Mar 12, 2024

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]. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2024

The p.V804L pathogenic mutation (also known as c.2410G>C), located in coding exon 14 of the RET gene, results from a G to C 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 (Bolino A et al. Oncogene, 1995 Jun;10:2415-9; Frohnauer MK et al. Surgery, 2000 Dec;128:1052-7;discussion 1057-8; Learoyd DL et al. Clin. Endocrinol. (Oxf), 2005 Dec;63:636-41; Maciel RMB et al. Endocr Connect, 2019 03;8:289-298). 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 has designated alterations at this codon occurring without additional RET mutations as moderate risk mutations (Wells SA et al. Thyroid. 2015 Jun;25(6):567-610; Kloos et al. Thyroid. 2009 June; 19(6):565-612). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

1.0

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

0.24

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

-0.33

N;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.0

N;N

REVEL

Pathogenic

0.72

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

0.98

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

Other links and lift over