rs201553718

Variant names:

• chr10-43112107-G-A
• rs201553718
• NM_020975.6:c.1531G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-43112107-G-A
• chr10-43112107-G-C
• chr10-43112107-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

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. 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:13 B:5
• Conservation: PhyloP100: 3.52
• Publications: 25 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: Orphanet, G2P
• multiple endocrine neoplasia type 2A

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), 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: Benign. The variant received -7 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 VariationId is 24883.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000177 (27/152382) while in subpopulation NFE AF = 0.000309 (21/68036). AF 95% confidence interval is 0.000207. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.1531G>A	p.Glu511Lys	missense_variant	Exon 8 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1531G>A	p.Glu511Lys	missense_variant	Exon 8 of 20	5	NM_020975.6	ENSP00000347942.3

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

GnomAD2 exomes AF: 0.000176 AC: 40 AN: 226932 AF XY: 0.000155

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.0000693 AC: 3 AN: 43262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25862

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39064

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 83912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.000336 AC: 372 AN: 1106248

Other (OTH) AF: 0.000534 AC: 32 AN: 59918

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

African (AFR) AF: 0.000144 AC: 6 AN: 41598

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000183 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:13 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple endocrine neoplasia type 2A Uncertain:3 Benign:2

Apr 23, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PS3, BS4 -

Nov 21, 2015

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Aug 03, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. 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). 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). it was also found in three first-degree relatives of one of the affected individuals, and all three individuals displayed normal biochemical parameters (PMID: 21551259). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Jun 23, 2025

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

May 16, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Uncertain:4

Jul 28, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Feb 01, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

not specified Uncertain:1 Benign:1

Jan 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 16, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Multiple endocrine neoplasia, type 2 Uncertain:1 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 16, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Aug 19, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 17, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 21, 2015

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Medullary thyroid carcinoma Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

RET-related disorder Uncertain:1

Nov 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		3.5
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
Mutation Taster		=36/64	disease causing

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

Other links and lift over

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