NM_000251.3(MSH2):c.1865C>G (p.Pro622Arg) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 11, 2024
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:: RCV000256112.6

Allele description [Variation Report for NM_000251.3(MSH2):c.1865C>G (p.Pro622Arg)]

NM_000251.3(MSH2):c.1865C>G (p.Pro622Arg)

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.1865C>G (p.Pro622Arg)

HGVS:

NC_000002.12:g.47475130C>G
NG_007110.2:g.77007C>G
NM_000251.3:c.1865C>GMANE SELECT
NM_001258281.1:c.1667C>G
NP_000242.1:p.Pro622Arg
NP_000242.1:p.Pro622Arg
NP_001245210.1:p.Pro556Arg
LRG_218t1:c.1865C>G
LRG_218:g.77007C>G
LRG_218p1:p.Pro622Arg
NC_000002.11:g.47702269C>G
NM_000251.1:c.1865C>G
NM_000251.2:c.1865C>G

Protein change:

P556R

Links:

dbSNP: rs28929483

NCBI 1000 Genomes Browser:

rs28929483

Molecular consequence:

NM_000251.3:c.1865C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1667C>G - 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
SCV000322563	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Dec 14, 2023)	germline	clinical testing	Citation Link,
SCV000601444	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	pathogenic (Sep 11, 2024)	unknown	clinical testing	PubMed (15) [See all records that cite these PMIDs] 34837403, 21309037, 20672385, 19267393, 18822302, 17720936, 16616355, 7717919, 8261515, 33357406, 22102614, 24362816, 26951660, 28874130, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000322563

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Dec 14, 2023)

germline

clinical testing

Citation Link,

SCV000601444

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

pathogenic
(Sep 11, 2024)

unknown

clinical testing

PubMed (15)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of SNPs in hMSH3/MSH6 interaction domain affecting the structure and function of MSH2 protein.

Singh S, Sharma S, Baranwal M.

Biotechnol Appl Biochem. 2022 Dec;69(6):2454-2465. doi: 10.1002/bab.2295. Epub 2021 Dec 15.

PubMed [citation]

PMID:: 34837403

Characterization of MSH2 variants by endogenous gene modification in mouse embryonic stem cells.

Wielders EA, Dekker RJ, Holt I, Morris GE, te Riele H.

Hum Mutat. 2011 Apr;32(4):389-96. doi: 10.1002/humu.21448. Epub 2011 Mar 8.

PubMed [citation]

PMID:: 21309037

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000322563.8

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

Description

Observed in a family reported to have Lynch syndrome (PMID: 28874130); Published functional studies suggest a damaging effect: resistance to 6-TG similar to known pathogenic variants (PMID: 33357406); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18822302, 21120944, 36550560, 28874130, 33357406)

#	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, SCV000601444.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

The MSH2 c.1865C>G (p.Pro622Arg) variant has been reported in the published literature in a family with Lynch syndrome (PMID: 28874130 (2017)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 33357406 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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, this variant is classified as pathogenic.

#	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: Nov 10, 2024

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