NM_020975.6(RET):c.785T>C (p.Val262Ala) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 4, 2020
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:: RCV000223157.11

Allele description [Variation Report for NM_020975.6(RET):c.785T>C (p.Val262Ala)]

NM_020975.6(RET):c.785T>C (p.Val262Ala)

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.785T>C (p.Val262Ala)

HGVS:

NC_000010.11:g.43105111T>C
NG_007489.1:g.33043T>C
NM_000323.2:c.785T>C
NM_001355216.2:c.23T>C
NM_001406743.1:c.785T>C
NM_001406744.1:c.785T>C
NM_001406759.1:c.785T>C
NM_001406760.1:c.785T>C
NM_001406761.1:c.656T>C
NM_001406762.1:c.656T>C
NM_001406763.1:c.785T>C
NM_001406764.1:c.656T>C
NM_001406765.1:c.785T>C
NM_001406766.1:c.497T>C
NM_001406767.1:c.497T>C
NM_001406768.1:c.656T>C
NM_001406769.1:c.785T>C
NM_001406770.1:c.497T>C
NM_001406772.1:c.785T>C
NM_001406774.1:c.656T>C
NM_020629.2:c.785T>C
NM_020630.7:c.785T>C
NM_020975.6:c.785T>CMANE SELECT
NP_000314.1:p.Val262Ala
NP_001342145.1:p.Val8Ala
NP_001342145.1:p.Val8Ala
NP_001393672.1:p.Val262Ala
NP_001393673.1:p.Val262Ala
NP_001393688.1:p.Val262Ala
NP_001393689.1:p.Val262Ala
NP_001393690.1:p.Val219Ala
NP_001393691.1:p.Val219Ala
NP_001393692.1:p.Val262Ala
NP_001393693.1:p.Val219Ala
NP_001393694.1:p.Val262Ala
NP_001393695.1:p.Val166Ala
NP_001393696.1:p.Val166Ala
NP_001393697.1:p.Val219Ala
NP_001393698.1:p.Val262Ala
NP_001393699.1:p.Val166Ala
NP_001393701.1:p.Val262Ala
NP_001393703.1:p.Val219Ala
NP_065680.1:p.Val262Ala
NP_065681.1:p.Val262Ala
NP_065681.1:p.Val262Ala
NP_065681.1:p.Val262Ala
NP_066124.1:p.Val262Ala
NP_066124.1:p.Val262Ala
LRG_518t1:c.785T>C
LRG_518t2:c.785T>C
LRG_518:g.33043T>C
LRG_518p1:p.Val262Ala
LRG_518p2:p.Val262Ala
NC_000010.10:g.43600559T>C
NM_001355216.1:c.23T>C
NM_020630.4:c.785T>C
NM_020630.6:c.785T>C
NM_020975.4:c.785T>C
NM_020975.5:c.785T>C

Protein change:

V166A

Links:

dbSNP: rs139790943

NCBI 1000 Genomes Browser:

rs139790943

Molecular consequence:

NM_000323.2:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.23T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.656T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.656T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.656T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.497T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.497T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.656T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.497T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.656T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000540171	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 24, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002068400	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 4, 2020)	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

SCV000540171

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 24, 2017)

germline

clinical testing

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

SCV002068400

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 4, 2020)

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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000540171.1

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

Description

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 4 papers, with comments suggesting VUS. It has been seen in unaffected patients, as well as one with Hirschprung's disease and an individual with pituitary adenomas but did not segregate in this family. This variant has a Max MAF of 0.032% in ExAC. It is classified with 2 stars as VUS by GeneDx, Invitae, Biesecker, and CSER_CC_NCGL.

#	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 Genetic Services Laboratory, University of Chicago, SCV002068400.1

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

Description

DNA sequence analysis of the RET gene demonstrated a sequence change, c.785T>C, in exon 4 that results in an amino acid change, p.Val262Ala. This sequence change has been described in the gnomAD database with a frequency of 0.043% in the South Asian sub-population (dbSNP rs139790943). The p.Val262Ala change has been reported in an individual with Hirshsprung's disease (PMID: 11955539). The p.Val262Ala change affects a moderately conserved amino acid residue located in a domain of the RET protein that is known to be functional. The p.Val262Ala substitution appears to be deleterious based on in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Val262Ala change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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