10-43114491-G-T

Position:

chr10-43114491-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_020975.6(RET):c.1891G>T(p.Asp631Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,852 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 (★★). Synonymous variant affecting the same amino acid position (i.e. D631D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.86

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

PP5

Variant 10-43114491-G-T is Pathogenic according to our data. Variant chr10-43114491-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 24914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43114491-G-T is described in Lovd as [Pathogenic]. Variant chr10-43114491-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6 linkuse as main transcript	c.1891G>T	p.Asp631Tyr	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.1891G>T	p.Asp631Tyr	missense_variant	11/20	5	NM_020975.6	ENSP00000347942	P4	P07949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

246932

Hom.:

AF XY:

0.00000747

AC XY:

AN XY:

133928

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:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454852

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724054

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 17, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 631 of the RET protein (p.Asp631Tyr). 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 individuals with clinical features of multiple endocrine neoplasia type 2 (PMID: 16839264). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24914). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects RET function (PMID: 10049754). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 08, 2022

May be associated with a moderate risk of aggressive medullary thyroid cancer compared to other pathogenic RET gain of function variants (PMID: 19469690); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: increased expression, aberrant phosphorylation, and high transforming activity (PMID: 34905813, 10049754); This variant is associated with the following publications: (PMID: 18062802, 24134185, 33219105, 22274720, 11149622, 16839264, 7608256, 14718397, 17923033, 18845906, 9506724, 24466223, 27809725, 30349395, 29625052, 34267909, 33362715, 34154310, 35676000, 35966080, 32571506, 32376047, 34439168, 10049754, 19469690, 36451132, 28747092, 28946813, 34905813, 14633923) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2023

The p.D631Y pathogenic mutation (also known as c.1891G>T) is located in coding exon 11 of the RET gene. This alteration results from a G to T substitution at nucleotide position 1891. The aspartic acid at codon 631 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been observed in multiple individuals and families diagnosed with pheochromocytoma (PCC) and/or medullary thyroid carcinoma (MTC) (Elston MS et al. Horm Metab Res. 2012 May;44(5):339-42), including two large Korean MEN2A families (Bae SJ et al. Thyroid. 2006 Jun;16(6):609-14) and in a woman diagnosed with metastatic MTC and a PCC at age 40 who also carried two other RET missense alterations (Koch, CA et al. Exp Clin Endocrinol Diabetes. 2000;108(8):493). Elston et al. observed that patients with this mutation typically present first with PCC and MTC may occur at a later onset than reported with other RET mutations (Elston MS et al. Horm Metab Res. 2012 May;44(5):339-42). Functional studies indicate that D631Y acts as a gain-of-function mutation by inducing ligand-independent Ret dimerization, a mechanism of action established in other mutations within the extracellular domain (Asai N et al. Biochem. Biophys. Res. Commun. 1999 Feb 24; 255(3):587-90). This mutation has been classified as conferring "moderate risk" for MTC by the American Thyroid Association (formerly categorized as Level B) (Wells SA et al. Thyroid. 2015 Jun; 25(6):567-610; Kloos RT et al. Thyroid. 2009 Jun; 19(6):565-612). This amino acid position is well 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

D;T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

T;T;T

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.6

D;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0080

D;D;D

Sift4G

Benign

0.12

T;D;T

Polyphen

1.0

D;.;D

Vest4

0.91

MutPred

0.79

Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);

MVP

0.98

MPC

0.26

ClinPred

0.98

GERP RS

3.6

Varity_R

0.59

gMVP

0.92

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