rs1064796534

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP3

The NM_020975.6(RET):c.59_61dupCGC(p.Pro20dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,511,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L21L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 35)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

RET
NM_020975.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.01

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

familial medullary thyroid carcinoma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
multiple endocrine neoplasia type 2A
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
multiple endocrine neoplasia type 2B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
pheochromocytoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Hirschsprung disease, susceptibility to, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Haddad syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hirschsprung disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
bilateral renal agenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
renal agenesis
Inheritance: AR Classification: LIMITED Submitted by: G2P

RET links:

ENSG00000303432 (HGNC:):

ENSG00000303432 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_020975.6

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.59_61dupCGC	p.Pro20dup	disruptive_inframe_insertion	Exon 1 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 link	c.59_61dupCGC	p.Pro20dup	disruptive_inframe_insertion	Exon 1 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151894

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:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000950

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000450

AC:

AN:

111212

AF XY:

0.0000488

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000147

AC:

AN:

1359348

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

670508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28824

American (AMR)

AF:

0.00

AC:

AN:

33426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24392

East Asian (EAS)

AF:

0.0000597

AC:

AN:

33526

South Asian (SAS)

AF:

0.00

AC:

AN:

76586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5158

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1067328

Other (OTH)

AF:

0.00

AC:

AN:

56806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151894

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41382

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000950

AC:

AN:

10522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67934

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 2

Uncertain:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.59_61dup, results in the insertion of 1 amino acid(s) of the RET protein (p.Pro20dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 423618). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Mar 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant causes an in-frame insertion of one amino acid in the RET protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 32091409). This variant has been identified in 6/142268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Feb 14, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.59_61dupCGC variant has not, to our knowledge, been published in the literature as pathogenic or benign. This in-frame duplication of three nucleotides in occurs in a region that is not conserved and is not located in a known functional domain. Since in-frame duplications may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider c.59_61dupCGC to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Aug 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.59_61dupCGC variant (also known as p.P20dup), located in coding exon 1 of the RET gene, results from an in-frame duplication of CGC at nucleotide positions 59 to 61. This results in the duplication of an extra proline residue between codons 20 and 21. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.0

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over