10-43118392-G-C

Variant names:

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

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>C​(p.Glu768Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 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: 6.8e-7 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• 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-C is Pathogenic according to our data. Variant chr10-43118392-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020975.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.2304G>C	p.Glu768Asp	missense	Exon 13 of 20	NP_066124.1
	RET	NM_001406743.1		c.2304G>C	p.Glu768Asp	missense	Exon 13 of 21	NP_001393672.1
	RET	NM_001406744.1		c.2304G>C	p.Glu768Asp	missense	Exon 13 of 20	NP_001393673.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.2304G>C	p.Glu768Asp	missense	Exon 13 of 20	ENSP00000347942.3
	RET	ENST00000340058.6	TSL:1	c.2304G>C	p.Glu768Asp	missense	Exon 13 of 19	ENSP00000344798.4
	RET	ENST00000713926.1		c.2040G>C	p.Glu680Asp	missense	Exon 13 of 19	ENSP00000519223.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461782 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 8.99e-7 AC: 1 AN: 1111970

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RET: PS1, PM1, PM2, PS4:Moderate, PS3:Supporting

Sep 12, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RET c.2304G>C; p.Glu768Asp variant (rs78014899) has been described in multiple individuals with medullary thyroid carcinoma (MTC; Aiello 2005, Eng 1995). This variant is reported in ClinVar (Variation ID: 13931) but is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 768 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, another variant resulting in the same amino acid change at this codon (c.2304G>T; p.Glu768Asp) has been described in individuals with MTC (Antinolo 2002, Millar 2011, Wiench 2001). In vitro functional studies of this variant indicate higher transforming capabilities when compared to wildtype (Pasini 1997). Based on available information, the p.Glu768Asp variant is considered pathogenic. REFERENCES Aiello A et al. The familial medullary thyroid carcinoma-associated RET E768D mutation in a multiple endocrine neoplasia type 2A case. Surgery. 2005 May;137(5):574-6. Antinolo G et al. A novel germline point mutation, c.2304 G-->T, in codon 768 of the RET proto-oncogene in a patient with medullary thyroid carcinoma. Am J Med Genet. 2002 Jun 1;110(1):85-7. Eng C et al. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene. 1995 Feb 2;10(3):509-13. Millar S et al. Familial pediatric endocrine tumors. Oncologist. 2011;16(10):1388-96. Pasini A et al. Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain. Oncogene. 1997 Jul 24;15(4):393-402. Wiench M et al. Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients. J Clin Oncol. 2001 Mar 1;19(5):1374-80.

Jun 24, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RET c.2304G>C (p.Glu768Asp) variant has been reported in the published literature in individuals with familial medullary thyroid cancer (FMTC) (PMIDs: 7784092 (1995), 7845675 (1995), 8918855 (1996), 9506724 (1998), 10445857 (1999), 16736292 (2006), 25810047 (2015), 29656518 (2018), 33340421 (2020)). Functional studies determined that this variant was damaging to protein function (PMIDs: 9242375 (1997) and 26046350 (2015)). 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.

Multiple endocrine neoplasia, type 2 Pathogenic:2

Mar 07, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RET function (PMID: 14715928, 15184865, 17047083, 26046350). 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. ClinVar contains an entry for this variant (Variation ID: 13931). 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. This variant is not present in population databases (gnomAD no frequency). 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). For these reasons, this variant has been classified as Pathogenic.

Familial medullary thyroid carcinoma Pathogenic:1

Jun 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 03, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E768D pathogenic mutation (also known as c.2304G>C), located in coding exon 13 of the RET gene, results from a G to C 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 reported to segregate with disease in several patients and families with medullary thyroid cancer and has been observed in two patients with a clinical diagnosis of MEN2A (Boccia LM et al. Clin. Genet. 1997 Feb;51:81-5; Eng C et al. Oncogene. 1995 Feb;10:509-13; Aiello A et al. Surgery. 2005 May;137:574-6; Antiñolo G et al. Am. J. Med. Genet. 2002 Jun;110:85-7; Bolino A et al. Oncogene. 1995 Jun;10:2415-9; Machens A et al. Hum. Mutat. 2018 06;39(6):860-869; Ambry internal data). In multiple assays testing RET function, this variant showed a modest level of RET activation and transforming capabilities when compared to wildtype (Pasini A et al. Oncogene, 1997 Jul;15:393-402; Arighi E et al. Mol Endocrinol. 2004 Apr;18:1004-17). 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unlikely.

Hepatocellular carcinoma Pathogenic:1

May 17, 2022

CZECANCA consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

Computational scores

Source: dbNSFP v4.9

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	0.84	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.015	D
MutationAssessor	Benign	0.69	N
PhyloP100		2.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.71
Sift	Benign	0.11	T
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.90
MutPred		0.84		Loss of glycosylation at P766 (P = 0.1366)
MVP		0.99
MPC		0.36
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; COSMIC: COSV60687895; COSMIC: COSV60687895;