NM_000251.3:c.942+17_942+29delAAAAAAAAAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000251.3(MSH2):c.942+17_942+29delAAAAAAAAAAAAA variant causes a intron change. The variant allele was found at a frequency of 0.00439 in 1,044,430 control chromosomes in the GnomAD database, including 107 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 101 hom., cov: 0)

Exomes 𝑓: 0.0021 ( 6 hom. )

Consequence

MSH2
NM_000251.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 6.75

Publications

4 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 -16 ACMG points.

BP6

Variant 2-47414420-TAAAAAAAAAAAAA-T is Benign according to our data. Variant chr2-47414420-TAAAAAAAAAAAAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 182601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.942+17_942+29delAAAAAAAAAAAAA		intron_variant	Intron 5 of 15	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.942+3_942+15delAAAAAAAAAAAAA		splice_region_variant, intron_variant	Intron 5 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes

AF:

0.0398

AC:

2482

AN:

62390

Hom.:

100

Cov.:

show subpopulations

Gnomad AFR

AF:

0.122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0181

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00980

Gnomad NFE

AF:

0.000311

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.0124

AC:

648

AN:

52420

AF XY:

0.00933

show subpopulations

Gnomad AFR exome

AF:

0.126

Gnomad AMR exome

AF:

0.00595

Gnomad ASJ exome

AF:

0.000801

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000639

Gnomad OTH exome

AF:

0.00335

GnomAD4 exome

AF:

0.00214

AC:

2102

AN:

982034

Hom.:

AF XY:

0.00187

AC XY:

915

AN XY:

488080

show subpopulations

African (AFR)

AF:

0.0805

AC:

1734

AN:

21528

American (AMR)

AF:

0.00455

AC:

AN:

18672

Ashkenazi Jewish (ASJ)

AF:

0.000880

AC:

AN:

14768

East Asian (EAS)

AF:

0.0000423

AC:

AN:

23650

South Asian (SAS)

AF:

0.000592

AC:

AN:

57418

European-Finnish (FIN)

AF:

0.000140

AC:

AN:

21454

Middle Eastern (MID)

AF:

0.000399

AC:

AN:

2506

European-Non Finnish (NFE)

AF:

0.0000676

AC:

AN:

783486

Other (OTH)

AF:

0.00462

AC:

178

AN:

38552

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

138

206

275

344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.0398

AC:

2485

AN:

62396

Hom.:

101

Cov.:

AF XY:

0.0424

AC XY:

1173

AN XY:

27654

show subpopulations

African (AFR)

AF:

0.122

AC:

2380

AN:

19528

American (AMR)

AF:

0.0181

AC:

AN:

4144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1768

East Asian (EAS)

AF:

0.00

AC:

AN:

1634

South Asian (SAS)

AF:

0.00

AC:

AN:

1104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

634

Middle Eastern (MID)

AF:

0.0100

AC:

AN:

100

European-Non Finnish (NFE)

AF:

0.000311

AC:

AN:

32194

Other (OTH)

AF:

0.0244

AC:

AN:

780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.636

Heterozygous variant carriers

146

218

291

364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:5

May 16, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 09, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is found in HEREDICANCER,COLYNCH-HEREDIC panel(s).

Mar 28, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

Mar 18, 2017

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.

Jun 26, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 14, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Breast and/or ovarian cancer

Benign:1

Apr 01, 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 24, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.7

Mutation Taster

=71/29

polymorphism (auto)

(source)

Splicing

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