10-43113628-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):c.1832G>T(p.Cys611Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C611G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.14

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 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_020975.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43113627-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 24897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 10-43113628-G-T is Pathogenic according to our data. Variant chr10-43113628-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 24899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1832G>T	p.Cys611Phe	missense_variant	10/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1832G>T	p.Cys611Phe	missense_variant	10/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461072 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726764

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 2A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)

May 21, 2023

- -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 28, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys611 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9230192, 20979234, 27809725, 28099363). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 24899). This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 8626834, 11331212, 20979234). 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 cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 611 of the RET protein (p.Cys611Phe). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2023

The p.C611F pathogenic mutation (also known as c.1832G>T), located in coding exon 10 of the RET gene, results from a G to T substitution at nucleotide position 1832. The cysteine at codon 611 is replaced by phenylalanine, an amino acid with highly dissimilar properties. Multiple mutations at codon 611 have been associated with Hirschsprung Disease (HSCR), Multiple Endocrine Neoplasia Type 2A (MEN2A), and Familial Medullary Thyroid Cancer (FMTC) (Eng C et al. JAMA. 1996 Nov;276:1575-9; Nishikawa M et al. Eur J Hum Genet. 2003 May;11(5):364-8). The p.C611F pathogenic mutation has been reported in numerous families diagnosed with MEN2A (Frank-Raue K et al. J. Clin. Endocrinol. Metab. 1996 May;81:1780-3; Siggelkow H et al. Eur. J. Endocrinol. 2001 May;144:467-73). The American Thyroid Association Guidelines Task Force has provided recommendations for individuals with RET gene mutations (Kloos et al. Thyroid. 2009 June; 19(6):565-612; Wells SA et al. Thyroid. 2015 Jun;25:567-610). This amino acid position is highly conserved in available vertebrate species. 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 unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.95		Loss of sheet (P = 0.0357);.;Loss of sheet (P = 0.0357);
MVP		0.98
MPC		0.93
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs377767397; hg19: chr10-43609076;