2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_000251.3(MSH2):c.942+27_942+29delAAA variant causes a intron change. The variant allele was found at a frequency of 0.156 in 949,752 control chromosomes in the GnomAD database, including 472 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 57 hom., cov: 0)

Exomes 𝑓: 0.16 ( 472 hom. )

Failed GnomAD Quality Control

Consequence

MSH2
NM_000251.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

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 -12 ACMG points.

BP6

Variant 2-47414420-TAAA-T is Benign according to our data. Variant chr2-47414420-TAAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 439908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 472 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.942+27_942+29delAAA		intron_variant	Intron 5 of 15	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.942+3_942+5delAAA		splice_region_variant, intron_variant	Intron 5 of 15	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0583

AC:

3632

AN:

62322

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0796

Gnomad AMI

AF:

0.0608

Gnomad AMR

AF:

0.0405

Gnomad ASJ

AF:

0.0102

Gnomad EAS

AF:

0.00245

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.0833

Gnomad MID

AF:

0.0200

Gnomad NFE

AF:

0.0549

Gnomad OTH

AF:

0.0398

GnomAD2 exomes

AF:

0.136

AC:

7135

AN:

52420

AF XY:

0.129

show subpopulations

Gnomad AFR exome

AF:

0.113

Gnomad AMR exome

AF:

0.177

Gnomad ASJ exome

AF:

0.139

Gnomad EAS exome

AF:

0.186

Gnomad FIN exome

AF:

0.0563

Gnomad NFE exome

AF:

0.123

Gnomad OTH exome

AF:

0.160

GnomAD4 exome

AF:

0.156

AC:

148191

AN:

949752

Hom.:

472

AF XY:

0.155

AC XY:

73276

AN XY:

471362

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.138

AC:

2872

AN:

20784

American (AMR)

AF:

0.143

AC:

2526

AN:

17690

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

2064

AN:

14242

East Asian (EAS)

AF:

0.167

AC:

3758

AN:

22500

South Asian (SAS)

AF:

0.146

AC:

8014

AN:

54750

European-Finnish (FIN)

AF:

0.155

AC:

3214

AN:

20768

Middle Eastern (MID)

AF:

0.159

AC:

386

AN:

2434

European-Non Finnish (NFE)

AF:

0.157

AC:

119391

AN:

759344

Other (OTH)

AF:

0.160

AC:

5966

AN:

37240

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.379

Heterozygous variant carriers

6585

13169

19754

26338

32923

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4920

9840

14760

19680

24600

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0583

AC:

3632

AN:

62324

Hom.:

Cov.:

AF XY:

0.0578

AC XY:

1594

AN XY:

27596

show subpopulations

African (AFR)

AF:

0.0796

AC:

1542

AN:

19372

American (AMR)

AF:

0.0405

AC:

168

AN:

4148

Ashkenazi Jewish (ASJ)

AF:

0.0102

AC:

AN:

1768

East Asian (EAS)

AF:

0.00245

AC:

AN:

1634

South Asian (SAS)

AF:

0.00998

AC:

AN:

1102

European-Finnish (FIN)

AF:

0.0833

AC:

AN:

636

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0549

AC:

1772

AN:

32276

Other (OTH)

AF:

0.0397

AC:

AN:

780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

144

289

433

578

722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Aug 07, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome 1

Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Nov 22, 2021

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.7

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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