rs201553718

chr10-43112107-G-Achr10-43112107-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_020975.6(RET):c.1531G>A(p.Glu511Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,601,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E511D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:2
• Conservation: PhyloP100: 3.52

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13844106).
• BP6: Variant 10-43112107-G-A is Benign according to our data. Variant chr10-43112107-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 24883.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=13, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1531G>A	p.Glu511Lys	missense_variant	8/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1531G>A	p.Glu511Lys	missense_variant	8/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152264 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

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: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000176 AC: 40 AN: 226932 Hom.: 0 AF XY: 0.000155 AC XY: 19 AN XY: 122932

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000585

Gnomad SAS exome AF: 0.0000357

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.000283 AC: 410 AN: 1449320 Hom.: 0 Cov.: 32 AF XY: 0.000257 AC XY: 185 AN XY: 719734

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000336

Gnomad4 OTH exome AF: 0.000534

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152382 Hom.: 0 Cov.: 34 AF XY: 0.000161 AC XY: 12 AN XY: 74522

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000116 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple endocrine neoplasia type 2A Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	May 31, 2022	The RET c.1531G>A (p.Glu511Lys) missense change has a maximum subpopulation frequency of 0.031% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in two individuals with medullary thyroid cancer (MTC) with no known family history of MTC or thyroid tumors (PMID: 20103606, 21551259). The variant was also found in three first-degree relatives of one of the affected individuals and all three individuals displayed normal biochemical parameters (PMID: 21551259). Functional assays have shown increased RET and ERK phosphorylation levels and transforming activity at intermediate levels between those of wild-type and a well-established pathogenic variant (PMID: 20103606, 21551259). In summary, the evidence currently available is insufficient to determine the role of this variant in multiple endocrine neoplasia. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 21, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 18, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 23, 2020	PM2, PS3, BS4 -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2023	Published functional studies demonstrate moderate increases in phosphorylation and transforming activity (Muzza et al., 2010; Prazeres et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with medullary thyroid cancer as well as other cancer types (Prazeres et al., 2011; Muzza et al., 2010; Lebeault et al., 2017; Yehia et al., 2018; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 24055113, 21834681, 24336963, 20103606, 21551259, 25637381, 21479187, 26332594, 17316110, 27807062, 28946813, 30758123, 34426522, 14633923, 30446652, 16712668, 29684080, 35264596) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 03, 2022	BS1 -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 16, 2020	Variant summary: RET c.1531G>A (p.Glu511Lys) results in a conservative amino acid change located in the extracellular domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 226932 control chromosomes. The observed variant frequency is approximately 4.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 phenotype (3.7e-05), strongly suggesting that the variant is benign. c.1531G>A has been reported in the literature in affected and unaffected individuals from a family with apparently sporadic MTC (AS-MTC) (Prazeres_2006 and 2011). Due to non-conclusive co-segregation, these reports do not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 2. At least two publications report in-vitro experimental evidence evaluating an impact on protein function. Both demonstrated increased RET and ERK phosphorylation levels and transforming activity at intermediate levels between wild-type and the well known p.Cys634Arg positive control (Muzza_2010, Prazeres_2011). However, these findings do not allow convincing conclusions about the variant effect in-vivo. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign for Multiple Endocrine Neoplasia Type 2. -
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 is present in HGMD in 6 papers with comments suggesting VUS and benign. It was seen in a proband with medullary thyroid carcinoma but was found in unaffected relatives. It is present in ExAC with a Max MAF of 0.03% (35/114960 European chrs). It is classified in ClinVar with 1 star as VUS by Invitae, CSER_CC_NCGL, and ARUP. 14 non-mammals have a Lys at this position. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 17, 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. -

Multiple endocrine neoplasia type 2B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Nov 21, 2015

- -

Multiple endocrine neoplasia, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 511 of the RET protein (p.Glu511Lys). This variant is present in population databases (rs201553718, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 20103606, 21551259). ClinVar contains an entry for this variant (Variation ID: 24883). 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 tolerated. Experimental studies have shown that this missense change affects RET function (PMID: 20103606, 21551259). 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. -

Medullary thyroid carcinoma Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

RET-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2023

The RET c.1531G>A variant is predicted to result in the amino acid substitution p.Glu511Lys. This variant has been identified in individuals with medullary thyroid cancer, but was also found in unaffected family members (Muzza et al. 2010. PubMed ID: 20103606; Prazeres et al. 2011. PubMed ID: 21551259). In vitro analysis showed that this variant resulted in increased transforming potential of NIH3T3 fibroblasts, and using a phosphospecific antibody, western blot showed that this variant more readily induced phosphorylation compared to wild type (Prazeres et al. 2011. PubMed ID: 21551259). This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/24883/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.81	N;N;N
REVEL	Uncertain	0.50
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.36	T;D;T
Polyphen		0.18	B;.;B
Vest4		0.23
MVP		0.99
MPC		0.23
ClinPred		0.059	T
GERP RS		4.8
Varity_R		0.23
gMVP		0.65

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: rs201553718; hg19: chr10-43607555; COSMIC: COSV60701393;