2-47410107-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000251.3(MSH2):c.380A>G(p.Asn127Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,613,580 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N127D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 127 hom., cov: 31)

Exomes 𝑓: 0.0024 ( 116 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:28O:1

Conservation

PhyloP100: 9.25

Publications

43 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 -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 34 uncertain in NM_000251.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0063515306).

BP6

Variant 2-47410107-A-G is Benign according to our data. Variant chr2-47410107-A-G is described in ClinVar as Benign. ClinVar VariationId is 36577.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.380A>G	p.Asn127Ser	missense_variant	Exon 3 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.380A>G	p.Asn127Ser	missense_variant	Exon 3 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes

AF:

0.0213

AC:

3240

AN:

152098

Hom.:

126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0740

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00747

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.00575

AC:

1444

AN:

251084

AF XY:

0.00406

show subpopulations

Gnomad AFR exome

AF:

0.0782

Gnomad AMR exome

AF:

0.00246

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000344

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00242

AC:

3533

AN:

1461364

Hom.:

116

Cov.:

AF XY:

0.00217

AC XY:

1579

AN XY:

726938

show subpopulations

African (AFR)

AF:

0.0817

AC:

2732

AN:

33436

American (AMR)

AF:

0.00327

AC:

146

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00180

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000197

AC:

AN:

86146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000204

AC:

227

AN:

1111732

Other (OTH)

AF:

0.00553

AC:

334

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

159

319

478

638

797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.0213

AC:

3248

AN:

152216

Hom.:

127

Cov.:

AF XY:

0.0203

AC XY:

1509

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0740

AC:

3074

AN:

41514

American (AMR)

AF:

0.00746

AC:

114

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68016

Other (OTH)

AF:

0.0138

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

152

304

457

609

761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0130

Hom.:

Bravo

AF:

0.0246

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0769

AC:

339

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00698

AC:

848

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:28Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

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

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

Significance:Benign

Review Status:no assertion criteria provided

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 10, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 11, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asn127Ser variant in MSH2 is classified as benign because it has been identified in 7.8% (1942/24960) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Benign on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 36577). ACMG/AMP Criteria applied: BA1.

Lynch syndrome 1

Uncertain:1Benign:5

Jul 24, 2014

Pathway Genomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 11, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

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

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.

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:4

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MSH2 p.Asn127Ser variant was identified in the literature in black, white and Hispanic populations with functional studies suggesting that the p.Asn127Ser variant, in isolation, does not compromise MMR. However in 2 studies, this variant was identified together with other missense substitutions (especially p.Ala328Pro), and demonstrated significantly decreased repair deficiency (Kantelinen 2012, Ollila 2008, Samowitz 2001). The variant was also identified in dbSNP (ID: rs17217772) â€šÃ„ÃºWith benign, uncertain significance alleleâ€šÃ„Ã¹ and is listed in the 1000 Genomes Project in 124 of 5000 chromosomes (frequency: 0.0248). The variant is also identified in the NHLBI Exome Sequencing Project (ESP) in 4 of 8600 European American (frequency: 00005) and in 339 of 4406 African American alleles (frequency: 0.077). The variant is listed in the Exome Aggregation Consortium (ExAC) database (released Mar 14, 2016) and identified in 848 of 121398 chromosomes of which 27 were homozygous (frequency: 0.007) or 791 of 10402 Africans (frequency: 0.076), 20 of 11578 Latino (frequency: 0.002), 29 of 66732 European (Non-Finish) (frequency: 0.0004), 4 of 16510 South Asian (frequency: 0.0002) and 4 in 908 (frequency: 0.004) in other, increasing the likelihood this could be a low frequency benign variant. The variant is listed in GeneInsight - COGR (1x as benign by LMM and 2x as benign by ARUP); ClinVar (listed as benign by InSIGHT, Laboratory for Molecular Medicine, Emory Genetics, Ambry Genetics, Mayo Clinic, Pathway Genomics LabCorp and by TMI with no clinical significance given); in Clinvitae (by EmyClass 1x as benign) and InSiGHT Colon Cancer Gene Variant Databases (LOVD) 34x as Class 1 - not pathogenic. In UMD, the variant was identified 23x as neutral with a co-occurring pathogenic MLH1 p.Pro649LeufsX12, increasing the likelihood that the p.Asn127Ser variant does not have clinical significance. The p.Asn127 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asn127Ser variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site; however, HumanSpliceFinder and MaxEntScan predict an altered 3' splice site in this region and we cannot eliminate the possibility of a novel cryptic splice site. 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 likely benign.

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 14574163, 28932927, 24728327, 27629256, 26951660, 27884173, 12624141, 20176959, 16237223, 18470917, 22949387, 18951462, 21120944, 17720936, 11606497, 25107687, 21056691, 18547406)

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Hereditary cancer-predisposing syndrome

Benign:4

Oct 10, 2017

True Health Diagnostics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 18, 2014

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 06, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

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.

Lynch syndrome

Benign:3

Dec 21, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:research

MAF >1%

Breast and/or ovarian cancer

Benign:1

Jul 02, 2021

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2

Benign:1

Apr 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;D;.;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;D;D;D

MetaRNN

Benign

0.0064

T;T;T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.8

H;.;.;.;.

PhyloP100

9.3

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.5

D;D;D;.;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D;D;.;D

Sift4G

Uncertain

0.0050

D;D;D;.;D

Vest4

0.85

ClinPred

0.10

GERP RS

4.6

Varity_R

0.91

gMVP

0.75

Mutation Taster

=68/32

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over