NM_000251.3(MSH2):c.211G>C (p.Gly71Arg) AND Lynch syndrome 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 14, 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:: RCV003453090.2

Allele description [Variation Report for NM_000251.3(MSH2):c.211G>C (p.Gly71Arg)]

NM_000251.3(MSH2):c.211G>C (p.Gly71Arg)

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.211G>C (p.Gly71Arg)

HGVS:

NC_000002.12:g.47403402G>C
NG_007110.2:g.5279G>C
NM_000251.3:c.211G>CMANE SELECT
NM_001258281.1:c.13G>C
NP_000242.1:p.Gly71Arg
NP_000242.1:p.Gly71Arg
NP_001245210.1:p.Gly5Arg
LRG_218t1:c.211G>C
LRG_218:g.5279G>C
LRG_218p1:p.Gly71Arg
NC_000002.11:g.47630541G>C
NM_000251.1:c.211G>C
NM_000251.2:c.211G>C
p.G71R

Protein change:

G5R

Links:

dbSNP: rs587782659

NCBI 1000 Genomes Browser:

rs587782659

Molecular consequence:

NM_000251.3:c.211G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.13G>C - 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
SCV004177083	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004186737	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Jul 26, 2023)	unknown	clinical testing	Citation Link,
SCV004194549	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 13, 2023)	unknown	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

SCV004177083

Clinical Genomics Laboratory, Washington University in St. Louis

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 14, 2023)

germline

clinical testing

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

SCV004186737

Myriad Genetics, Inc.

criteria provided, single submitter

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

Likely pathogenic
(Jul 26, 2023)

unknown

clinical testing

Citation Link,

SCV004194549

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 13, 2023)

unknown

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	unknown	unknown	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

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 Clinical Genomics Laboratory, Washington University in St. Louis, SCV004177083.1

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

Description

The MSH2 c.211G>C (p.Gly71Arg) variant has been reported in two individuals affected with Lynch syndrome (Vargas-Parra GM et al., PMID: 28577310). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant falls on the last nucleotide of exon 1, which is part of the consensus splice site for this exon. Functional studies show that the variant results in a partial deletion of exon 1, which is predicted to generate a truncated protein (p.Tyr66Serfs*10), and impacts protein function (Vargas-Parra GM et al., PMID: 28577310). Computational predictors indicate that this variant would alter splicing, evidence that correlates to an impact of this variant on MSH2 function. This variant has been reported in the ClinVar database as a likely pathogenic variant by five submitters and pathogenic by one submitter. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

#	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 Myriad Genetics, Inc., SCV004186737.1

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

Description

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].

#	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

From Baylor Genetics, SCV004194549.1

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

Last Updated: Jun 23, 2024

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Relating variation to medicine