NM_000251.3(MSH2):c.192C>G (p.Ile64Met) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 10, 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:: RCV003999635.2

Allele description [Variation Report for NM_000251.3(MSH2):c.192C>G (p.Ile64Met)]

NM_000251.3(MSH2):c.192C>G (p.Ile64Met)

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.192C>G (p.Ile64Met)

HGVS:

NC_000002.12:g.47403383C>G
NG_007110.2:g.5260C>G
NM_000251.3:c.192C>GMANE SELECT
NM_001258281.1:c.-7C>G
NP_000242.1:p.Ile64Met
NP_000242.1:p.Ile64Met
LRG_218t1:c.192C>G
LRG_218:g.5260C>G
LRG_218p1:p.Ile64Met
NC_000002.11:g.47630522C>G
NM_000251.2:c.192C>G

Protein change:

I64M

Links:

dbSNP: rs1395172053

NCBI 1000 Genomes Browser:

rs1395172053

Molecular consequence:

NM_001258281.1:c.-7C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000251.3:c.192C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004832016	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jul 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32694065, 33357406, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004832016

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jul 10, 2023)

germline

clinical testing

PubMed (3)
[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	108544	not provided	clinical testing

Citations

PubMed

Lynch syndrome identification in a Brazilian cohort of endometrial cancer screened by a universal approach.

Rosa RCA, Santis JO, Teixeira LA, Molfetta GA, Dos Santos JTT, Ribeiro VDS, Chahud F, Ribeiro-Silva A, Brunaldi MO, Silva WA Jr, Ferraz VEF.

Gynecol Oncol. 2020 Oct;159(1):229-238. doi: 10.1016/j.ygyno.2020.07.013. Epub 2020 Jul 18.

PubMed [citation]

PMID:: 32694065

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

See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004832016.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces isoleucine with methionine at codon 64 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with endometrial cancer (PMID: 32694065; Rosa et al. abstract TL-016, CBGM 2019). 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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