NM_020975.6(RET):c.509C>T (p.Thr170Ile) AND Multiple endocrine neoplasia, type 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000701145.11

Allele description [Variation Report for NM_020975.6(RET):c.509C>T (p.Thr170Ile)]

NM_020975.6(RET):c.509C>T (p.Thr170Ile)

Gene:

RET:ret proto-oncogene [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q11.21

Genomic location:

Preferred name:

NM_020975.6(RET):c.509C>T (p.Thr170Ile)

HGVS:

NC_000010.11:g.43102513C>T
NG_007489.1:g.30445C>T
NM_000323.2:c.509C>T
NM_001406743.1:c.509C>T
NM_001406744.1:c.509C>T
NM_001406759.1:c.509C>T
NM_001406760.1:c.509C>T
NM_001406761.1:c.380C>T
NM_001406762.1:c.380C>T
NM_001406763.1:c.509C>T
NM_001406764.1:c.380C>T
NM_001406765.1:c.509C>T
NM_001406768.1:c.380C>T
NM_001406769.1:c.509C>T
NM_001406771.1:c.509C>T
NM_001406772.1:c.509C>T
NM_001406773.1:c.509C>T
NM_001406774.1:c.380C>T
NM_001406779.1:c.509C>T
NM_001406780.1:c.509C>T
NM_001406781.1:c.509C>T
NM_001406782.1:c.509C>T
NM_001406783.1:c.380C>T
NM_001406785.1:c.509C>T
NM_001406786.1:c.380C>T
NM_001406787.1:c.509C>T
NM_020629.2:c.509C>T
NM_020630.7:c.509C>T
NM_020975.6:c.509C>TMANE SELECT
NP_000314.1:p.Thr170Ile
NP_001393672.1:p.Thr170Ile
NP_001393673.1:p.Thr170Ile
NP_001393688.1:p.Thr170Ile
NP_001393689.1:p.Thr170Ile
NP_001393690.1:p.Thr127Ile
NP_001393691.1:p.Thr127Ile
NP_001393692.1:p.Thr170Ile
NP_001393693.1:p.Thr127Ile
NP_001393694.1:p.Thr170Ile
NP_001393697.1:p.Thr127Ile
NP_001393698.1:p.Thr170Ile
NP_001393700.1:p.Thr170Ile
NP_001393701.1:p.Thr170Ile
NP_001393702.1:p.Thr170Ile
NP_001393703.1:p.Thr127Ile
NP_001393708.1:p.Thr170Ile
NP_001393709.1:p.Thr170Ile
NP_001393710.1:p.Thr170Ile
NP_001393711.1:p.Thr170Ile
NP_001393712.1:p.Thr127Ile
NP_001393714.1:p.Thr170Ile
NP_001393715.1:p.Thr127Ile
NP_001393716.1:p.Thr170Ile
NP_065680.1:p.Thr170Ile
NP_065681.1:p.Thr170Ile
NP_065681.1:p.Thr170Ile
NP_065681.1:p.Thr170Ile
NP_066124.1:p.Thr170Ile
NP_066124.1:p.Thr170Ile
LRG_518t1:c.509C>T
LRG_518t2:c.509C>T
LRG_518:g.30445C>T
LRG_518p1:p.Thr170Ile
LRG_518p2:p.Thr170Ile
NC_000010.10:g.43597961C>T
NM_020630.4:c.509C>T
NM_020630.6:c.509C>T
NM_020975.4:c.509C>T

Protein change:

T127I

Links:

dbSNP: rs200547906

NCBI 1000 Genomes Browser:

rs200547906

Molecular consequence:

NM_000323.2:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406787.1:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Multiple endocrine neoplasia, type 2 (MEN2)
Identifiers:: MONDO: MONDO:0019003; MedGen: C4048306

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000829929	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 8, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004827582	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000829929

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 8, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004827582

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 1, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000829929.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 170 of the RET protein (p.Thr170Ile). This variant is present in population databases (rs200547906, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 41844). 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. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004827582.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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