NM_020975.6(RET):c.1189G>A (p.Val397Met) AND Multiple endocrine neoplasia, type 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 30, 2024
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:: RCV000534092.11

Allele description [Variation Report for NM_020975.6(RET):c.1189G>A (p.Val397Met)]

NM_020975.6(RET):c.1189G>A (p.Val397Met)

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.1189G>A (p.Val397Met)

HGVS:

NC_000010.11:g.43109156G>A
NG_007489.1:g.37088G>A
NM_000323.2:c.1189G>A
NM_001355216.2:c.427G>A
NM_001406743.1:c.1189G>A
NM_001406744.1:c.1189G>A
NM_001406759.1:c.1189G>A
NM_001406760.1:c.1189G>A
NM_001406761.1:c.1060G>A
NM_001406762.1:c.1060G>A
NM_001406763.1:c.1189G>A
NM_001406764.1:c.1060G>A
NM_001406765.1:c.1189G>A
NM_001406766.1:c.901G>A
NM_001406767.1:c.901G>A
NM_001406768.1:c.1060G>A
NM_001406770.1:c.901G>A
NM_001406771.1:c.751G>A
NM_001406773.1:c.751G>A
NM_001406775.1:c.463G>A
NM_001406776.1:c.463G>A
NM_001406777.1:c.463G>A
NM_001406778.1:c.463G>A
NM_001406784.1:c.199G>A
NM_020629.2:c.1189G>A
NM_020630.7:c.1189G>A
NM_020975.6:c.1189G>AMANE SELECT
NP_000314.1:p.Val397Met
NP_001342145.1:p.Val143Met
NP_001342145.1:p.Val143Met
NP_001393672.1:p.Val397Met
NP_001393673.1:p.Val397Met
NP_001393688.1:p.Val397Met
NP_001393689.1:p.Val397Met
NP_001393690.1:p.Val354Met
NP_001393691.1:p.Val354Met
NP_001393692.1:p.Val397Met
NP_001393693.1:p.Val354Met
NP_001393694.1:p.Val397Met
NP_001393695.1:p.Val301Met
NP_001393696.1:p.Val301Met
NP_001393697.1:p.Val354Met
NP_001393699.1:p.Val301Met
NP_001393700.1:p.Val251Met
NP_001393702.1:p.Val251Met
NP_001393704.1:p.Val155Met
NP_001393705.1:p.Val155Met
NP_001393706.1:p.Val155Met
NP_001393707.1:p.Val155Met
NP_001393713.1:p.Val67Met
NP_065680.1:p.Val397Met
NP_065681.1:p.Val397Met
NP_065681.1:p.Val397Met
NP_065681.1:p.Val397Met
NP_066124.1:p.Val397Met
NP_066124.1:p.Val397Met
LRG_518t1:c.1189G>A
LRG_518t2:c.1189G>A
LRG_518:g.37088G>A
LRG_518p1:p.Val397Met
LRG_518p2:p.Val397Met
NC_000010.10:g.43604604G>A
NM_001355216.1:c.427G>A
NM_020630.4:c.1189G>A
NM_020630.6:c.1189G>A
NM_020975.4:c.1189G>A

Protein change:

V143M

Links:

dbSNP: rs183729115

NCBI 1000 Genomes Browser:

rs183729115

Molecular consequence:

NM_000323.2:c.1189G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.427G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.1189G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.1189G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.1189G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.1189G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.1060G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.1060G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.1189G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.1060G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.1189G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.901G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.901G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.1060G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.901G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.751G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.751G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.463G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.463G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.463G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.463G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.199G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.1189G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.1189G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.1189G>A - 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
SCV000658394	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 30, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22174939, 28492532
SCV005430322	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Mar 24, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22174939, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000658394

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 30, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005430322

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Mar 24, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	143475	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

RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients.

So MT, Leon TY, Cheng G, Tang CS, Miao XP, Cornes BK, Diem NN, Cui L, Ngan ES, Lui VC, Wu XZ, Wang B, Wang H, Yuan ZW, Huang LM, Li L, Xia H, Zhu D, Liu J, Nguyen TL, Chan IH, Chung PH, et al.

PLoS One. 2011;6(12):e28986. doi: 10.1371/journal.pone.0028986. Epub 2011 Dec 9.

PubMed [citation]

PMID:: 22174939
PMCID:: PMC3235168

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000658394.5

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

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 397 of the RET protein (p.Val397Met). This variant is present in population databases (rs183729115, gnomAD 0.007%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 22174939). ClinVar contains an entry for this variant (Variation ID: 477307). 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, SCV005430322.1

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

Description

This missense variant replaces valine with methionine at codon 397 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Hirschsprung disease (PMID: 22174939). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	143475	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 16, 2025

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