NM_000251.3(MSH2):c.2210+1G>C AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 7, 2022
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:: RCV003584546.1

Allele description [Variation Report for NM_000251.3(MSH2):c.2210+1G>C]

NM_000251.3(MSH2):c.2210+1G>C

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.2210+1G>C

HGVS:

NC_000002.12:g.47476572G>C
NG_007110.2:g.78449G>C
NM_000251.3:c.2210+1G>CMANE SELECT
NM_001258281.1:c.2012+1G>C
NM_001406631.1:c.2210+1G>C
NM_001406632.1:c.2210+1G>C
NM_001406633.1:c.2210+1G>C
NM_001406634.1:c.2210+1G>C
NM_001406635.1:c.2210+1G>C
NM_001406636.1:c.2177+1G>C
NM_001406637.1:c.2210+1G>C
NM_001406638.1:c.2249+1G>C
NM_001406639.1:c.2210+1G>C
NM_001406640.1:c.2210+1G>C
NM_001406641.1:c.2210+1G>C
NM_001406642.1:c.2210+1G>C
NM_001406643.1:c.2210+1G>C
NM_001406644.1:c.2210+1G>C
NM_001406645.1:c.2210+1G>C
NM_001406646.1:c.2210+1G>C
NM_001406647.1:c.2060+1G>C
NM_001406648.1:c.2210+1G>C
NM_001406649.1:c.2060+1G>C
NM_001406650.1:c.2060+1G>C
NM_001406651.1:c.2060+1G>C
NM_001406652.1:c.2060+1G>C
NM_001406653.1:c.2150+1G>C
NM_001406654.1:c.1790+1G>C
NM_001406656.1:c.1313+1G>C
NM_001406658.1:c.854+1G>C
NM_001406659.1:c.854+1G>C
NM_001406660.1:c.854+1G>C
NM_001406661.1:c.854+1G>C
NM_001406662.1:c.854+1G>C
NM_001406669.1:c.854+1G>C
NM_001406674.1:c.2210+1G>C
LRG_218t1:c.2210+1G>C
LRG_218:g.78449G>C
NC_000002.11:g.47703711G>C
NM_000251.1:c.2210+1G>C
NM_000251.2:c.2210+1G>C

Links:

dbSNP: rs267608002

NCBI 1000 Genomes Browser:

rs267608002

Molecular consequence:

NM_000251.3:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001258281.1:c.2012+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406631.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406632.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406633.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406634.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406635.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406636.1:c.2177+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406637.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406638.1:c.2249+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406639.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406640.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406641.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406642.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406643.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406644.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406645.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406646.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406647.1:c.2060+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406648.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406649.1:c.2060+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406650.1:c.2060+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406651.1:c.2060+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406652.1:c.2060+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406653.1:c.2150+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406654.1:c.1790+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406656.1:c.1313+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406658.1:c.854+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406659.1:c.854+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406660.1:c.854+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406661.1:c.854+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406662.1:c.854+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406669.1:c.854+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406674.1:c.2210+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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LOC118369680 [Oncorhynchus keta]
LOC118369680 [Oncorhynchus keta]
Gene ID:118369680

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004356727	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 7, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11879922, 16451135, 17189986, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004356727

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 7, 2022)

germline

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation analysis of MLH1 and MSH2 genes performed by denaturing high-performance liquid chromatography.

Kurzawski G, Safranow K, Suchy J, Chlubek D, Scott RJ, Lubiński J.

J Biochem Biophys Methods. 2002 Mar 4;51(1):89-100.

PubMed [citation]

PMID:: 11879922

Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).

Kurzawski G, Suchy J, Lener M, Kłujszo-Grabowska E, Kładny J, Safranow K, Jakubowska K, Jakubowska A, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Oszutowska D, Kowalska E, Góźdź S, Niepsuj S, Słomski R, Pławski A, Łacka-Wojciechowska A, Rozmiarek A, et al.

Clin Genet. 2006 Jan;69(1):40-7.

PubMed [citation]

PMID:: 16451135

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV004356727.1

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

Description

This variant causes a G to C nucleotide substitution at the +1 position of intron 13 of the MSH2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This alteration has been reported to result in out-of-frame skipping of exon 13 (PMID: 11879922, 16451135), creating a frameshift and premature translation stop signal and expected to result in an absent or non-functional protein product. This variant has been observed in an individual with colorectal cancer that exhibited microsatellite instability and loss of MLH1 and MSH2 proteins by immunohistochemistry analyses (PMID: 17189986), and in families affected by hereditary non-polyposis colorectal cancer (PMID: 11879922, 16451135). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c.2210+1G>T and c.2210+1G>A, are known to be disease-causing (ClinVar variation ID: 820897, 90921). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely 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

Last Updated: Feb 20, 2024

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