10-43121967-A-G

Position:

• chr10-43121967-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):​c.2752A>G​(p.Met918Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,302 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M918T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.31

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43121968-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 10-43121967-A-G is Pathogenic according to our data. Variant chr10-43121967-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.2752A>G	p.Met918Val	missense_variant	16/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2752A>G	p.Met918Val	missense_variant	16/20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461302 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727016

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 07, 2023	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 918 of the RET protein (p.Met918Val). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of RET-related conditions (PMID: 20516206, 21810974, 25440022, 27807060, 28946813, 33827484). It has also been observed to segregate with disease in related individuals. However, it has been observed in individuals without personal history of RET-related conditions (PMID: 27807060, 21810974). One study that prospectively screened individuals with this variant identified several with medullary thyroid cancer or C-cell hyperplasia (PMID: 27807060). ClinVar contains an entry for this variant (Variation ID: 38614). 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 does not substantially affect RET function (PMID: 9075701, 21810974). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2024	Variant summary: RET c.2752A>G (p.Met918Val) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251478 control chromosomes. c.2752A>G has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma (e.g. Martins-Costa_2016). 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. The most pronounced variant effect showed a moderate effect on cell growth in transfected cells and a metabolomic profile consistent with a moderate risk (Veyrat-Durebex_2019). The following publications have been ascertained in the context of this evaluation (PMID: 27807060, 30653460). ClinVar contains an entry for this variant (Variation ID: 38614). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This missense variant replaces methionine with valine at codon 918 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown this variant does not increase transforming ability or cell proliferation (PMID: 9075701, 21810974), one study showed an increase in colony formation compared to wild-type RET (PMID: 21810974). This variant has been reported in at least 13 individuals affected with medullary thyroid cancer (PMID: 20516206, 27807060, 28946813, 30624503, 30763276, 33827484). This variant has been shown to segregate with disease in two families, but has also been observed in unaffected individuals (PMID: 27807060). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Met918Thr, is a well-documented pathogenic mutation (ClinVar variation ID: 13919), indicating that methionine at this position is important for RET protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9075701, 22429913, 23180660, 28698189, 27539727, 20516206, 27807060, 37321569, 25440022, 14633923, 30624503, 31510104, 30763276, 21810974, 33827484, 28946813) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 26, 2023	In the published literature, this variant has been reported to segregate in affected families with medullary thyroid cancer (PMIDs: 30763276 (2019) and 33827484 (2021)) and C-cell hyperplasia (PMID: 27807060 (2016)). Functional analysis yielded inconclusive results regarding the impact of this variant on protein function (PMID: 9075701 (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 (i.e., MutationTaster and PolyPhen-2) 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Multiple endocrine neoplasia type 2A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Mar 01, 2023

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30624503, 21810974, 28946813, 33827484]. Functional studies indicate this variant impacts protein function [PMID: 30653460]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2024

The p.M918V variant (also known as c.2752A>G), located in coding exon 16 of the RET gene, results from an A to G substitution at nucleotide position 2752. The methionine at codon 918 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in numerous individuals with a personal and/or family history of medullary thyroid carcinoma (MTC) (Cosci B et al. Endocr. Relat. Cancer. 2011 Oct;18:603-12; Lebeault M et al. Thyroid. 2017 12;27:1511-1522; Martins-Costa MC et al. Endocr. Relat. Cancer. 2016 12;23:909-920; Martins-Costa MC et al. Arch Endocrinol Metab. 2018;62:623-635; Romei C et al. Eur. J. Endocrinol. 2010 Aug;163:301-8). In one study, two unaffected family members were found to be carriers of the p.M918V variant and in vitro functional studies showed low to no transforming activity from this variant. Authors propose that this alteration may confer a more moderate disease risk as compared to other RET mutations (Cosci B et al. Endocr. Relat. Cancer. 2011 Oct;18:603-12). 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 likely 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	0.79
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.95		Loss of MoRF binding (P = 0.1151);Loss of MoRF binding (P = 0.1151);
MVP		0.99
MPC		0.78
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs377767442; hg19: chr10-43617415;