NM_000251.3(MSH2):c.2053A>T (p.Ile685Leu) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 20, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001872015.6

Allele description [Variation Report for NM_000251.3(MSH2):c.2053A>T (p.Ile685Leu)]

NM_000251.3(MSH2):c.2053A>T (p.Ile685Leu)

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.2053A>T (p.Ile685Leu)

HGVS:

NC_000002.12:g.47476414A>T
NG_007110.2:g.78291A>T
NM_000251.3:c.2053A>TMANE SELECT
NM_001258281.1:c.1855A>T
NP_000242.1:p.Ile685Leu
NP_001245210.1:p.Ile619Leu
LRG_218t1:c.2053A>T
LRG_218:g.78291A>T
NC_000002.11:g.47703553A>T
NM_000251.2:c.2053A>T

Protein change:

I619L

Links:

dbSNP: rs1060499876

NCBI 1000 Genomes Browser:

rs1060499876

Molecular consequence:

NM_000251.3:c.2053A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1855A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002113913	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33357406, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002113913

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 20, 2023)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.

Jia X, Burugula BB, Chen V, Lemons RM, Jayakody S, Maksutova M, Kitzman JO.

Am J Hum Genet. 2021 Jan 7;108(1):163-175. doi: 10.1016/j.ajhg.2020.12.003. Epub 2020 Dec 23.

PubMed [citation]

PMID:: 33357406
PMCID:: PMC7820803

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002113913.3

#	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 isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 685 of the MSH2 protein (p.Ile685Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1171156). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. 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

Last Updated: Sep 29, 2024

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