2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000251.3(MSH2):c.942+16_942+29delAAAAAAAAAAAAAA variant causes a intron change. The variant allele was found at a frequency of 0.000302 in 1,044,324 control chromosomes in the GnomAD database, including 1 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 0.000032 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

MSH2
NM_000251.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

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 -8 ACMG points.

BP6

Variant 2-47414420-TAAAAAAAAAAAAAA-T is Benign according to our data. Variant chr2-47414420-TAAAAAAAAAAAAAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 491848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.942+16_942+29delAAAAAAAAAAAAAA		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+16delAAAAAAAAAAAAAA		splice_region_variant, intron_variant	Intron 5 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes

AF:

0.0000321

AC:

AN:

62234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000516

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00129

GnomAD4 exome

AF:

0.000319

AC:

313

AN:

982088

Hom.:

AF XY:

0.000291

AC XY:

142

AN XY:

488126

show subpopulations

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

African (AFR)

AF:

0.0108

AC:

233

AN:

21522

American (AMR)

AF:

0.00118

AC:

AN:

18676

Ashkenazi Jewish (ASJ)

AF:

0.000135

AC:

AN:

14772

East Asian (EAS)

AF:

0.0000423

AC:

AN:

23652

South Asian (SAS)

AF:

0.000104

AC:

AN:

57450

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2506

European-Non Finnish (NFE)

AF:

0.0000217

AC:

AN:

783504

Other (OTH)

AF:

0.000830

AC:

AN:

38550

⚠️ 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: 0.338

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000321

AC:

AN:

62236

Hom.:

Cov.:

AF XY:

0.0000725

AC XY:

AN XY:

27570

show subpopulations

African (AFR)

AF:

0.0000516

AC:

AN:

19372

American (AMR)

AF:

0.00

AC:

AN:

4140

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:

0.00

AC:

AN:

100

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

32194

Other (OTH)

AF:

0.00128

AC:

AN:

780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:2

Jun 26, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome

Benign:1

Sep 04, 2023

All of Us Research Program, National Institutes of Health

Significance: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

=86/14

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over