10-43118392-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. 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 (★★).

• 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:7
• Conservation: PhyloP100: 2.45

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• 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 id is 13931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43118392-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

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

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.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

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. -

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 -

Multiple endocrine neoplasia, type 2 Pathogenic:1

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 v4.3

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	0.84	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.015	D
MutationAssessor	Benign	0.69	N;N
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
Polyphen		0.99	D;D
Vest4		0.90
MutPred		0.84		Loss of glycosylation at P766 (P = 0.1366);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

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

Other links and lift over

dbSNP: rs78014899; hg19: chr10-43613840; COSMIC: COSV60687895; COSMIC: COSV60687895;