rs143795581

chr10-43114596-A-Cchr10-43114596-A-Gchr10-43114596-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_020975.6(RET):c.1996A>C(p.Lys666Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,828 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K666E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.33

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43114596-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1996A>C	p.Lys666Gln	missense_variant	11/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1996A>C	p.Lys666Gln	missense_variant	11/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250846 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135632

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460828 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726732

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Lys666 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15858153, 20103606, 21690267, 26269449, 27673361). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1045072). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 31510104). This variant is present in population databases (rs143795581, gnomAD 0.006%). This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 666 of the RET protein (p.Lys666Gln). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2020

The p.K666Q variant (also known as c.1996A>C), located in coding exon 11 of the RET gene, results from an A to C substitution at nucleotide position 1996. The lysine at codon 666 is replaced by glutamine, an amino acid with similar properties. In one study, this alteration was detected in an Italian patient with medullary thyroid cancer (MTC) (Elisei R et al. Genes (Basel), 2019 09;10:). Similar alterations affecting this same amino acid, p.K666N and p.K666E, have been reported in multiple MTC patients and families (Xu JY et al. Thyroid. 2016 Oct, epub; Currás-Freixes M et al. J. Med. Genet., 2015 Oct;52:647-56; Ahmed SA et al. J Mol Diagn 2005;7:283-8). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for p.K666Q alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.053	T;T
Sift4G	Benign	0.080	T;T
Polyphen		0.97	D;D
Vest4		0.75
MutPred		0.70		Loss of methylation at K666 (P = 0.0018);Loss of methylation at K666 (P = 0.0018);
MVP		0.86
MPC		0.74
ClinPred		0.76	D
GERP RS		4.8
Varity_R		0.21
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143795581; hg19: chr10-43610044;