rs145170911

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_020975.6(RET):​c.2611G>A​(p.Val871Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,613,782 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).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

2
6
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:3

Conservation

PhyloP100: 6.89
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.16509777).
BP6
Variant 10-43120084-G-A is Benign according to our data. Variant chr10-43120084-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41842.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=8}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RETNM_020975.6 linkuse as main transcriptc.2611G>A p.Val871Ile missense_variant 15/20 ENST00000355710.8 NP_066124.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RETENST00000355710.8 linkuse as main transcriptc.2611G>A p.Val871Ile missense_variant 15/205 NM_020975.6 ENSP00000347942 P4P07949-1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152208
Hom.:
0
Cov.:
33
show subpopulations
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:
0.000828
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000840
AC:
21
AN:
250112
Hom.:
0
AF XY:
0.0000738
AC XY:
10
AN XY:
135490
show subpopulations
Gnomad AFR exome
AF:
0.000186
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000426
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000105
AC:
153
AN:
1461456
Hom.:
0
Cov.:
34
AF XY:
0.000109
AC XY:
79
AN XY:
727018
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.000441
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000890
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.0000919
AC:
14
AN:
152326
Hom.:
0
Cov.:
33
AF XY:
0.0000671
AC XY:
5
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000172
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000124
AC:
15

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 10, 2023In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with medullary thyroid carcinoma and in an individual with breast cancer (Elisei et al., 2019; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 22703879, 26034076, 24336963, 31822803, 14633923, 37375228, 31510104, 35264596) -
Uncertain significance, no assertion criteria providedresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 13, 2012- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 24, 2013- -
Multiple endocrine neoplasia type 2A Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Apr 18, 2023This 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 submitterclinical testingCounsylSep 07, 2016- -
Likely benign, criteria provided, single submitterclinical testingMendelicsApr 09, 2024- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 27, 2021This alteration is classified as 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 submittercurationSema4, Sema4Dec 11, 2021- -
Multiple endocrine neoplasia type 2B Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylSep 07, 2016- -
Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1275808:Congenital central hypoventilation;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 02, 2022- -
Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 871 of the RET protein (p.Val871Ile). This variant is present in population databases (rs145170911, gnomAD 0.05%), 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: 31510104). ClinVar contains an entry for this variant (Variation ID: 41842). 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. 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. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 21, 2023Variant summary: RET c.2611G>A (p.Val871Ile) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250112 control chromosomes. The observed variant frequency is approximately 2-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.2611G>A has been reported in the literature in individuals affected with hereditary medullary thyroid carcinoma, breast cancer, congenital anomalies of the kidney and urinary tract, and atherosclerosis, with no strong evidence for causality (example, Elisei_2019, Guindalini_2022, Hwang_2014, Johnston_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31510104, 35264596, 24429398, 22703879). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=8, Benign, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Uncertain
24
DANN
Uncertain
1.0
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.34
T
M_CAP
Uncertain
0.26
D
MetaRNN
Benign
0.17
T
MetaSVM
Uncertain
0.13
D
MutationTaster
Benign
1.0
D;D
Sift4G
Benign
0.091
T
Vest4
0.23
MVP
0.92
ClinPred
0.21
T
GERP RS
5.4

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145170911; hg19: chr10-43615532; API