10-43114546-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_020975.6(RET):c.1946C>T(p.Ser649Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000445 in 1,610,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S649S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:18 O:1
• Conservation: PhyloP100: 7.70

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_benign. Variant got -1 ACMG points.

• BP6: Variant 10-43114546-C-T is Benign according to our data. Variant chr10-43114546-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 24928.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=14, Uncertain_significance=5, Benign=3, not_provided=1}. Variant chr10-43114546-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1946C>T	p.Ser649Leu	missense_variant	11/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1946C>T	p.Ser649Leu	missense_variant	11/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000316 AC: 79 AN: 249656 Hom.: 0 AF XY: 0.000274 AC XY: 37 AN XY: 135064

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000503

Gnomad NFE exome AF: 0.000572

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000452 AC: 659 AN: 1458682 Hom.: 0 Cov.: 32 AF XY: 0.000475 AC XY: 345 AN XY: 725794

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000159

Gnomad4 NFE exome AF: 0.000549

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74418

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000765

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000499 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000321 AC: 39

EpiCase AF: 0.000709

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:18 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 10, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 06, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 31, 2022	BS1, BP2, PP3 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	RET: BS2 -

not specified Uncertain:1 Benign:3 Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 23, 2021	Variant summary: RET c.1946C>T (p.Ser649Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 251656 control chromosomes. The observed variant frequency is approximately 61 fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma phenotype (5.6e-06), strongly suggesting that the variant is benign. c.1946C>T has been reported in the literature in individuals affected with sporadic/familial Medullary Thyroid Carcinoma/Hirschsprung's disease and in some instances in unaffected family members when tested (example, Wiench_2001, Vierhapper_2004, Colombo-Benkmann_2008, deGroot_2006, Vaclavikova_2009, Waldman_2009, Erlic_2010, Innella_2020). These data do not allow any conclusion about variant significance. Multiple co-occurrences in trans with other pathogenic variant(s) have been reported in the citations ascertained above (example, RET c.1902C>G, p.Cys634Trp; RET c.1901G>A, p.Cys634Tyr; RET c.2410G>A, p.Val804Met; RET c.2410G>C, p.Val804Leu), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Colombo-Benkmann_2008). The most pronounced variant effect results in a mild transforming potential and constitutive TK activity, and stimulation of growth of NIH3T3 cells. This resulted in its classification as a level 1 RET variant, namely low penetrance of MTC, a relatively low aggressive potential of the disease (level 1), and rare further endocrinopathies. In summary, this was historically considered a "mild" mutation in MTC since penetrance seemed quite low, disease phenotype was milder than in MEN2/2A, and prognosis was good in patients with this variant; however, the interpretation changed when Erlic_2010 reported data strongly suggesting it is NOT pathogenic: 1) variant was incidentally found in the healthy sister of a p.C634Y MTC/PHEO patient during family testing for p.C634Y; 2) variant was found at significant frequencies in European and American normals. The non-pathogenicity of this variant is supported by the fact that in multiple reported MTC cases, it has co-occurred with true pathogenic variants, with reports that the two mutations together did not aggravate disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments but a majority concordance towards a benign/likely benign outcome (n=8) (VUS, n=6). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 10, 2022	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been classified as DM in HGMD related to elevated basal serum calcitonin. It has been reported in 12 papers, with 2 related to Hirschprung disease. The comments suggest that it is not pathogenic. This variant is present at 0.05% in ExAC. It is classified in ClinVar with 1 star as Likely benign/Benign by Invitae and Children's Mercy Hospital, and as VUS by Ambry and ARUP. Variant occurs at greater frequency in population than expected for disorder -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 19, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 21, 2021	- -

Multiple endocrine neoplasia type 2A Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 18, 2023	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 16, 2018	- -

Multiple endocrine neoplasia, type 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 18, 2022	- -

Appendicitis Uncertain:1

Uncertain significance, no assertion criteria provided

research

Klinik und Poliklinik für Kinderchirurgie, Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus

Dec 17, 2020

- -

Pheochromocytoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 15, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Elevated basal serum calcitonin Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Renal hypodysplasia/aplasia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 15, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hirschsprung disease, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 15, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Multiple endocrine neoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 15, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.046	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.82
MVP		0.98
MPC		0.46
ClinPred		0.18	T
GERP RS		4.3
Varity_R		0.27
gMVP		0.78

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: rs148935214; hg19: chr10-43609994; COSMIC: COSV60687010;