NM_000251.3(MSH2):c.339G>A (p.Lys113=) AND Lynch syndrome

Germline classification:: Benign (4 submissions)
Last evaluated:: Sep 5, 2013
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000030252.12

Allele description [Variation Report for NM_000251.3(MSH2):c.339G>A (p.Lys113=)]

NM_000251.3(MSH2):c.339G>A (p.Lys113=)

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.339G>A (p.Lys113=)

Other names:

p.K113K:AAG>AAA

HGVS:

NC_000002.12:g.47408528G>A
NG_007110.2:g.10405G>A
NM_000251.3:c.339G>AMANE SELECT
NM_001258281.1:c.141G>A
NP_000242.1:p.Lys113=
NP_000242.1:p.Lys113=
NP_001245210.1:p.Lys47=
LRG_218t1:c.339G>A
LRG_218:g.10405G>A
LRG_218p1:p.Lys113=
NC_000002.11:g.47635667G>A
NM_000251.1:c.339G>A
NM_000251.2:c.339G>A
NM_000251.3:c.339G>A
NP_000242.1:p.(=)
p.K113K

Links:

dbSNP: rs35898375

NCBI 1000 Genomes Browser:

rs35898375

Molecular consequence:

NM_000251.3:c.339G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001258281.1:c.141G>A - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV000052919	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	no assertion criteria provided	Benign (Oct 1, 2012)	germline	clinical testing
SCV000107598	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	no known pathogenicity (Sep 5, 2013)	germline	research	Citation Link,
SCV000212175	CSER _CC_NCGL, University of Washington - CSER - NEXT Medicine variant annotation	criteria provided, single submitter (Amendola et al. (Genome Res. 2015))	Benign (Mar 11, 2015)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000592461	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Likely benign	unknown	clinical testing

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, research
not provided	unknown	yes	0	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052919.2

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

#	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

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000107598.3

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

Description

Synonymous variant with no effect on splicing, MAF 0.01-1% & >3 MSS/MSH2 IHC normal CRC tumours. Multifactorial likelihood analysis posterior probability <0.001

#	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

From CSER _CC_NCGL, University of Washington - CSER - NEXT Medicine variant annotation, SCV000212175.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	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

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592461.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	0	not provided	not provided	clinical testing	not provided

Description

The MSH2 p.Lys113Lys variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant was identified in the literature in 5 of 744 proband chromosomes (frequency 0.007) from individuals with colon cancer and was absent in 180 control chromosomes evaluated from these studies (Liu 1998, Palicio 2002, Pastrello 2011, Tournier 2008). The variant was also identified in dbSNP (ID: rs35898375) â€šÃ„ÃºWith probable-non-pathogenic alleleâ€šÃ„Ã¹, â€šÃ„ÃºMismatch Repair Genes Variant Databaseâ€šÃ„Ã¹, â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹, â€šÃ„ÃºMMR Gene Unclassified Variants Databaseâ€šÃ„Ã¹ and UMD (11X as a neutral variant). Within the UMD listing, the variant is listed to co-occur with a known pathogenic mutation in MSH2 (c.1058del, p.Lys353ArgfsX4), increasing the likelihood that this variant does not have clinical importance. Pastrello (2011) found this variant in three families that were Amsterdam-like or met Amsterdam I criteria; in all three cases the variant was found to co-occur with a pathogenic mutation in either MLH1 or MSH2. In one of the three families, the variant was determined to be in trans with a pathogenic MSH2 mutation, and the tumour showed loss of heterozygosity of the p.Lys113Lys variant allele, further increasing the likelihood of the variant not having clinical importance. In addition, one functional assay demonstrated no effect of this variant on splicing, which was concordant with analysis of patient RNA (Tournier 2008). Finally, the variant was reported in the 1000 Genomes project with a frequency of 0.002 and in the ClinSeq project with a frequency of 0.007, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		0	not provided	not provided	not provided

Last Updated: May 1, 2024

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