rs377767429

Variant names:

• chr10-43120120-GC-TT
• rs377767429
• NM_020975.6:c.2647_2648delGCinsTT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PP3 PP5_Very_Strong

The NM_020975.6(RET):​c.2647_2648delGCinsTT​(p.Ala883Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. A883P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.91
• Publications: 137 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_020975.6
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 10-43120120-GC-TT is Pathogenic according to our data. Variant chr10-43120120-GC-TT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.2647_2648delGCinsTT	p.Ala883Phe	missense_variant		ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2647_2648delGCinsTT	p.Ala883Phe	missense_variant		5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 2B Pathogenic:1

May 21, 2023

Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Jun 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 883 of the RET protein (p.Ala883Phe). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2 (PMID: 9294615, 25244518, 28323957). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 38629). 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: 10679286). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Nov 29, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PS2_very_strong, PS3_supporting, PS4_moderate -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 05, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2647_2648delGCinsTT pathogenic mutation (also known as p.A883F), located in coding exon 15 of the RET gene, results from an in-frame deletion of GC and insertion of TT at nucleotide positions 2647 to 2648. This results in the substitution of the alanine residue for a phenylalanine residue at codon 883, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals clinically diagnosed with MEN 2B with a personal and/or family history that is consistent with RET-related disease, and was reported as de novo in at least 2 unrelated probands (Smith DP et al. Oncogene, 1997 Sep;15:1213-7; Gimm O et al. J Clin Endocrinol Metab, 1997 Nov;82:3902-4; Jasim S et al. Thyroid, 2011 Feb;21:189-92; Mathiesen JS et al. Thyroid, 2015 Jan;25:139-40; Raue F et al. J Clin Endocrinol Metab, 2018 Jan;103:235-243; Fussey JM et al. Clin Endocrinol (Oxf), 2021 Aug;95:295-302). One functional study demonstrated high transforming activity without dimerization for p.A883F (Iwashita T et al. Oncogene, 1999 Jul;18:3919-22). Another study demonstrated that p.A883F exerted ligand-independent autophosphorylation and showed a sensitivity profile similar to known pathogenic RET alterations (Carlomagno F et al. Oncogene, 2004 Aug;23:6056-63). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). 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
PhyloP100		7.9
Mutation Taster		=1/99	disease causing

Splicing

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

Other links and lift over

dbSNP: rs377767429; hg19: chr10-43615568; COSMIC: COSV60699157;