NM_000251.3(MSH2):c.1943T>A (p.Ile648Asn) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 1, 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:: RCV000523371.6

Allele description [Variation Report for NM_000251.3(MSH2):c.1943T>A (p.Ile648Asn)]

NM_000251.3(MSH2):c.1943T>A (p.Ile648Asn)

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.1943T>A (p.Ile648Asn)

HGVS:

NC_000002.12:g.47475208T>A
NG_007110.2:g.77085T>A
NM_000251.3:c.1943T>AMANE SELECT
NM_001258281.1:c.1745T>A
NP_000242.1:p.Ile648Asn
NP_000242.1:p.Ile648Asn
NP_001245210.1:p.Ile582Asn
LRG_218t1:c.1943T>A
LRG_218:g.77085T>A
LRG_218p1:p.Ile648Asn
NC_000002.11:g.47702347T>A
NM_000251.1:c.1943T>A
NM_000251.2:c.1943T>A

Protein change:

I582N

Links:

dbSNP: rs763100088

NCBI 1000 Genomes Browser:

rs763100088

Molecular consequence:

NM_000251.3:c.1943T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1745T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000618299	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Sep 1, 2023)	germline	clinical testing	Citation Link,
SCV002046202	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jun 22, 2023)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27601186, 33471991, 18990764, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000618299

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Sep 1, 2023)

germline

clinical testing

Citation Link,

SCV002046202

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Jun 22, 2023)

unknown

clinical testing

PubMed (4)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.

Lagerstedt-Robinson K, Rohlin A, Aravidis C, Melin B, Nordling M, Stenmark-Askmalm M, Lindblom A, Nilbert M.

Oncol Rep. 2016 Nov;36(5):2823-2835. doi: 10.3892/or.2016.5060. Epub 2016 Sep 1.

PubMed [citation]

PMID:: 27601186

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000618299.3

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27720647, 27601186, 24728327, 18822302, 21120944, 33357406, 18990764)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002046202.2

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

Description

In the published literature, this variant has been reported in individuals and families with colorectal cancer (PMID: 18990764 (2008)), Lynch syndrome (PMID: 27601186 (2016)), and breast cancer (PMID: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/MSH2)). The frequency of this variant in the general population, 0.000044 (5/113734 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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: Sep 29, 2024

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