Genetic Variant MSH2:p.Leu191Leu (chr2-47410300-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000251.3(MSH2):c.573C>T(p.Leu191Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,614,056 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. L191L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 88 hom., cov: 31)

Exomes 𝑓: 0.0019 ( 92 hom. )

Consequence

MSH2
NM_000251.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:24

Conservation

PhyloP100: 1.27

Publications

9 publications found

Variant links:

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

MSH2 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
Lynch syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
mismatch repair cancer syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 2-47410300-C-T is Benign according to our data. Variant chr2-47410300-C-T is described in ClinVar as Benign. ClinVar VariationId is 91140.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=1.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0618 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MSH2	NM_000251.3	MANE Select	c.573C>T	p.Leu191Leu	synonymous	Exon 3 of 16	NP_000242.1
MSH2	NM_001406674.1		c.573C>T	p.Leu191Leu	synonymous	Exon 3 of 18	NP_001393603.1
MSH2	NM_001406631.1		c.573C>T	p.Leu191Leu	synonymous	Exon 3 of 18	NP_001393560.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MSH2	ENST00000233146.7	TSL:1 MANE Select	c.573C>T	p.Leu191Leu	synonymous	Exon 3 of 16	ENSP00000233146.2
MSH2	ENST00000406134.5	TSL:1	c.573C>T	p.Leu191Leu	synonymous	Exon 3 of 16	ENSP00000384199.1
MSH2	ENST00000645506.1		c.573C>T	p.Leu191Leu	synonymous	Exon 3 of 17	ENSP00000495455.1

Frequencies

GnomAD3 genomes

AF:

0.0181

AC:

2757

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0639

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00475

AC:

1195

AN:

251458

AF XY:

0.00353

show subpopulations

Gnomad AFR exome

AF:

0.0667

Gnomad AMR exome

AF:

0.00246

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00190

AC:

2783

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

1171

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0712

AC:

2384

AN:

33480

American (AMR)

AF:

0.00255

AC:

114

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000185

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1112004

Other (OTH)

AF:

0.00391

AC:

236

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

168

336

505

673

841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0181

AC:

2761

AN:

152180

Hom.:

Cov.:

AF XY:

0.0177

AC XY:

1316

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0638

AC:

2647

AN:

41496

American (AMR)

AF:

0.00550

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68030

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

136

272

407

543

679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00553

Hom.:

Bravo

AF:

0.0205

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:24

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:9

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MSH2 p.Leu191= variant was identified in the following databases: dbSNP (ID: rs1800151) â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar (classified benign, reviewed by an expert panel (2013); submitters benign by InSIGHT, Ambry Genetics, Prevention Genetics, Invitae, Quest Diagnostics Nichols Institute San Juan Capistrano, ARUP, and Mayo Clinic, and likely benign by Illumina), Clinvitae (3x), Cosmic (in numerous primary tissue type tumours), UMD-LSDB (7x as neutral, co-occurring with pathogenic variants MSH2 c.1_211del (p.Met1?) and MSH6 c.2150_2153delTCAG (p.Val717AlafsX18)), Insight Colon Cancer Gene Variant Database (3x class 1), Mismatch Repair Genes Variant Database (2x), Insight Hereditary Tumors Database (4x), and in control databases in 1690 (48 homozygous) of 277178 chromosomes at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1576 of 24014 chromosomes (freq: 0.07), Other in 12 of 6462 chromosomes (freq: 0.002), Latino in 86 of 34420 chromosomes (freq: 0.002), European Non-Finnish in 12 of 126694 chromosomes (freq: 0.0001), and South Asian in 4 of 30782 chromosomes (freq: 0.0001), while not observed in the Ashkenazi Jewish, East Asian, and European Finnish populations. The variant was not identified in GeneInSight-COGR, MutDB, OR Zhejiang Colon Cancer Database. The p.Leu191= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 31, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Lynch syndrome 1

Benign:5

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 23, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Dec 04, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.

Apr 06, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:4

Nov 18, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Jan 24, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 21, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

Apr 13, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breast and/or ovarian cancer

Benign:1

Jul 12, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lynch syndrome

Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:research

MAF >1%

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

8.9

(source)

DANN

Benign

0.58

PhyloP100

1.3

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over