NM_000251.3(MSH2):c.482T>A (p.Val161Asp) AND Lynch syndrome 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 9, 2018
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000076607.4

Allele description [Variation Report for NM_000251.3(MSH2):c.482T>A (p.Val161Asp)]

NM_000251.3(MSH2):c.482T>A (p.Val161Asp)

Gene:

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.482T>A (p.Val161Asp)

HGVS:

NC_000002.12:g.47410209T>A
NG_007110.2:g.12086T>A
NM_000251.3:c.482T>AMANE SELECT
NM_001258281.1:c.284T>A
NP_000242.1:p.Val161Asp
NP_000242.1:p.Val161Asp
NP_001245210.1:p.Val95Asp
LRG_218t1:c.482T>A
LRG_218:g.12086T>A
LRG_218p1:p.Val161Asp
NC_000002.11:g.47637348T>A
NM_000251.1:c.482T>A
NM_000251.2:c.482T>A
P43246:p.Val161Asp
c.482T>A

Protein change:

V161D

Links:

UniProtKB: P43246#VAR_012936; dbSNP: rs63750126

NCBI 1000 Genomes Browser:

rs63750126

Molecular consequence:

NM_000251.3:c.482T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.284T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Lynch syndrome 1
Synonyms:: COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 1; MSH2-Related Hereditary Non-Polyposis Colon Cancer; Lynch syndrome I; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007356; MedGen: C2936783; Orphanet: 144; OMIM: 120435

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000107643	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v2.3)	Pathogenic (Mar 9, 2018)	germline	curation	Citation Link,
SCV004186630	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Jul 27, 2023)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17101317, 26951660, 15849733, 28785832 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000107643

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v2.3)

Pathogenic
(Mar 9, 2018)

germline

curation

Citation Link,

SCV004186630

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Likely pathogenic
(Jul 27, 2023)

unknown

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein.

Ollila S, Sarantaus L, Kariola R, Chan P, Hampel H, Holinski-Feder E, Macrae F, Kohonen-Corish M, Gerdes AM, Peltomäki P, Mangold E, de la Chapelle A, Greenblatt M, Nyström M.

Gastroenterology. 2006 Nov;131(5):1408-17. Epub 2006 Aug 22.

PubMed [citation]

PMID:: 17101317

Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants.

Houlleberghs H, Dekker M, Lantermans H, Kleinendorst R, Dubbink HJ, Hofstra RM, Verhoef S, Te Riele H.

Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):4128-33. doi: 10.1073/pnas.1520813113. Epub 2016 Mar 7.

PubMed [citation]

PMID:: 26951660
PMCID:: PMC4839441

See all PubMed Citations (4)

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000107643.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

Class 5 - Pathogenic Classification using multifactorial probability: 0.9977

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

From Myriad Genetics, Inc., SCV004186630.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 17101317, 26951660]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15849733, 28785832].

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

Last Updated: May 1, 2024

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