10-43118392-G-T

Variant names:

• chr10-43118392-G-T
• rs78014899
• NM_020975.6:c.2304G>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS1_Very_Strong PM2 PP3_Moderate PP5_Very_Strong

The NM_020975.6(RET):​c.2304G>T​(p.Glu768Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,782 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 the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E768E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.45
• Publications: 72 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 20 ACMG points.

• PS1: Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 10-43118392-G-T is Pathogenic according to our data. Variant chr10-43118392-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 38611.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.2304G>T	p.Glu768Asp	missense_variant	Exon 13 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2304G>T	p.Glu768Asp	missense_variant	Exon 13 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461782 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 2A Pathogenic:2

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 29, 2015

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Multiple endocrine neoplasia type 2B Pathogenic:1

Dec 29, 2015

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

MEN2 phenotype: Unclassified Pathogenic:1

Oct 27, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RET c.2304G>T (p.Glu768Asp) results in a conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251258 control chromosomes. c.2304G>T has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2 or familial medullary thyroid carcinoma. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant was autophosphorylated and displayed a transforming activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Multiple endocrine neoplasia, type 2 Pathogenic:1

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 768 of the RET protein (p.Glu768Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with medullary thyroid carcinoma (PMID: 9263528, 11230481, 12116277, 15855933, 16736292, 17097365, 18062802; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38611). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RET function (PMID: 14715928, 15184865, 17047083, 26046350). For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1

Oct 16, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RET c.2304G>T (p.Glu768Asp) variant has been reported in the published literature in individuals and families with medullary thyroid cancer (MTC) (PMID: 31510104 (2019), 21934104 (2011), 20516206 (2010), 17895320 (2007), 16736292 (2006), 12116277 (2002), 12016484 (2002), 11230481 (2001)), Hirschsprung's disease (PMID: 31510104 (2019)), Multiple endocrine neoplasia, type 2A (MEN 2A) (PMID: 20516206 (2010)), and Multiple endocrine neoplasia, type 2B (MEN 2B) (PMID: 29077903 (2018)). Functional studies reported this variant results in increased transforming activity and moderate oncogenic RET activation (PMID: 14715928 (2004), 9242375 (1997)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 23, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E768D pathogenic mutation (also known as c.2304G>T), located in coding exon 13 of the RET gene, results from a G to T substitution at nucleotide position 2304. The glutamic acid at codon 768 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been identified in multiple individuals with apparently sporadic medullary thyroid cancer as well as familial medullary thyroid cancer (Wiench M et al. J. Clin. Oncol. 2001 Mar;19:1374-80; Antiñolo G et al. Am. J. Med. Genet. 2002 Jun;110:85-7; Miyauchi A et al. World J Surg. 2002 Aug;26:1023-8; Dabir T et al. Fam Cancer. 2006;5:201-4; Elisei R et al. J. Clin. Endocrinol. Metab. 2007 Dec;92:4725-9; Millar S et al. Oncologist. 2011 Sep;16:1388-96). This alteration was also detected in a woman with MTC, cutaneous neuromas, and macular amyloidosis (Baykal C et al. J Am Acad Dermatol. 2007 Feb;56:S33-7). This variant affects the tyrosine kinase domain and results in a moderate level of RET activation with its oncogenic capacity dependent on the presence of GDNF (Arighi E et al. Mol Endocrinol. 2004 Apr;18(4):1004-17). In addition, a different nucleotide change resulting in the same amino acid substitution (c.2304G>C p.E768D) has been reported to segregate with disease in several families with medullary thyroid cancer, and has been observed in two patients with a clinical diagnosis of MEN2A (Eng C et al. Oncogene. 1995 Feb;10:509-13; Bolino A et al. Oncogene. 1995 Jun;10:2415-9; Boccia LM et al. Clin. Genet. 1997 Feb;51:81-5; Antiñolo G et al. Am. J. Med. Genet. 2002 Jun;110:85-7; Aiello A et al. Surgery. 2005 May;137:574-6). Furthermore, this alteration has been classified as conferring "moderate risk" for MTC by the American Thyroid Association (Wells SA. Thyroid. 2015 Jun; 25(6):567-610). 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, 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	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.80	D;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.69	N;N
PhyloP100		2.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.71
Sift	Benign	0.11	T;D
Sift4G	Benign	0.16	T;T
Vest4		0.90
ClinPred		0.98	D
GERP RS		2.7
Varity_R		0.62
gMVP		0.84
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs78014899; hg19: chr10-43613840;