NM_020975.6:c.1998G>T

Variant names:

• chr10-43114598-G-T
• rs146646971
• NM_020975.6:c.1998G>T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS1_Very_Strong PS3 PM5 PP3 PP5_Very_Strong

The NM_020975.6(RET):​c.1998G>T​(p.Lys666Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,836 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 (★★). ClinVar reports functional evidence for this variant: "SCV000329490: Published functional studies demonstrate increased tyrosine phosphorylation activity, kinase activity, and transforming potential compared to wild-type (Muzza et al., 2010)" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K666delinsNS) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:2
• Conservation: PhyloP100: 1.53
• Publications: 23 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: G2P, Orphanet
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, 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 23 ACMG points.

• PS1: Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329490: Published functional studies demonstrate increased tyrosine phosphorylation activity, kinase activity, and transforming potential compared to wild-type (Muzza et al., 2010); SCV000886052: However, functional analyses of the p.Lys666Asn variant protein show increased kinase and transforming activity (Muzza 2010). PMID: 20103606; SCV004220039: Additionally, functional studies have observed oncogenic effects resulting from this variant (PMID: 20103606 (2010)).; SCV000840058: Functional studies showed this variant displays high kinase and transforming activities [PMID: 20103606].; SCV004930740: Functional studies indicate this variant impacts protein function [PMID: 20103606].; SCV000543812: Experimental studies have shown that this missense change affects RET function (PMID: 20103606).; SCV000966948: "In vitro functional studies support an impact on protein function" (Muzza 2010 PMID:20103606); SCV002572242: At least one publication reports experimental evidence evaluating an impact on protein function (Muzza_2010). The most pronounced variant effect results in a 13-fold increased rate of phosphorylation compared to WT-RET consistent with a gain of function mechanism of disease.; SCV004357239: "A functional study has reported that this variant protein resulted in elevated kinase and cell transformation activities that were intermediate between the wild-type protein and the pathogenic control p.Cys634Arg (PMID: 20103606)."; SCV005045704: Functional analysis of this variant showed increased kinase and transforming activities in transfected HEK293 cells (PMID: 20103606).; SCV005430368: "A functional study has reported that this variant protein resulted in elevated kinase and cell transformation activities that were intermediate between the wild-type protein and the pathogenic control p.Cys634Arg (PMID: 20103606)."; SCV000674739: Analysis has demonstrated increased oncogenic potential as compared to wild type, as well as significant structural impact that was predicted to alter the transmembrane α-helix, likely changing the secondary structure of the protein (Muzza, 2010).; SCV004046293: Functional studies suggest this missense variant increases ERK and RET phosphorylation and cellular transformation (PMID: 20103606).; SCV004177183: Functional analyses of the p.Lys666Asn variant protein show increased kinase and transforming activity (Muzza M et al., PMID: 20103606).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43114598-G-TTCT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1897685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767
• PP5: Variant 10-43114598-G-T is Pathogenic according to our data. Variant chr10-43114598-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 24932.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.1998G>T	p.Lys666Asn	missense	Exon 11 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.1998G>T	p.Lys666Asn	missense	Exon 11 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.1998G>T	p.Lys666Asn	missense	Exon 11 of 20	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.1998G>T	p.Lys666Asn	missense	Exon 11 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.1998G>T	p.Lys666Asn	missense	Exon 11 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000615310.5	TSL:5	c.1602G>T	p.Lys534Asn	missense	Exon 9 of 17	ENSP00000480088.2	A0A087WWB1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250810 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1460780 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 726704

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52322

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

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1112006

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

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74256

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000924 Hom.: 4

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Multiple endocrine neoplasia, type 2 (6)
6	-	-	not provided (6)
3	-	-	Multiple endocrine neoplasia type 2A (3)
1	-	-	Familial medullary thyroid carcinoma (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hirschsprung disease, susceptibility to, 1 (1)
1	-	-	Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 (1)
1	-	-	Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma (1)
1	-	-	RET-related disorder (1)
-	-	-	Familial medullary thyroid carcinoma;C4048306:Multiple endocrine neoplasia, type 2 (1)
-	-	-	Multiple endocrine neoplasia type 2A;C3888239:Hirschsprung disease, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	0.058
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.83		Loss of methylation at K666 (P = 0.0018)
MVP		0.86
MPC		0.78
ClinPred		0.67	D
GERP RS		1.6
Varity_R		0.38
gMVP		0.83
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs146646971; hg19: chr10-43610046;