2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAAAAA

Variant names:

Variant summary

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

The ENST00000233146.7(MSH2):c.942+2_942+3insAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). The gene MSH2 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000048 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

MSH2
ENST00000233146.7 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.32

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, Orphanet, ClinGen
Lynch syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
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

new If you want to explore the variant's impact on the transcript ENST00000233146.7, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for MSH2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP6

Variant 2-47414420-T-TAA is Benign according to our data. Variant chr2-47414420-T-TAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1685779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000233146.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MSH2	NM_000251.3	MANE Select	c.942+28_942+29dupAA	intron	N/A	NP_000242.1	P43246-1
MSH2	NM_001406674.1		c.942+28_942+29dupAA	intron	N/A	NP_001393603.1
MSH2	NM_001406631.1		c.942+28_942+29dupAA	intron	N/A	NP_001393560.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MSH2	ENST00000233146.7	TSL:1 MANE Select	c.942+2_942+3insAA	splice_region intron	N/A	ENSP00000233146.2	P43246-1
MSH2	ENST00000406134.5	TSL:1	c.942+2_942+3insAA	splice_region intron	N/A	ENSP00000384199.1	E9PHA6
MSH2	ENST00000918107.1		c.993+2_993+3insAA	splice_region intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes

AF:

0.0000482

AC:

AN:

62230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000612

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000621

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000224

AC:

220

AN:

981752

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

104

AN XY:

487964

show subpopulations

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

African (AFR)

AF:

0.000185

AC:

AN:

21586

American (AMR)

AF:

0.000321

AC:

AN:

18666

Ashkenazi Jewish (ASJ)

AF:

0.000339

AC:

AN:

14768

East Asian (EAS)

AF:

0.000254

AC:

AN:

23636

South Asian (SAS)

AF:

0.000453

AC:

AN:

57404

European-Finnish (FIN)

AF:

0.0000932

AC:

AN:

21448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2506

European-Non Finnish (NFE)

AF:

0.000206

AC:

161

AN:

783196

Other (OTH)

AF:

0.000259

AC:

AN:

38542

⚠️ 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: 0.277

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000482

AC:

AN:

62230

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

27562

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

19366

American (AMR)

AF:

0.00

AC:

AN:

4136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1768

East Asian (EAS)

AF:

0.000612

AC:

AN:

1634

South Asian (SAS)

AF:

0.00

AC:

AN:

1108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

102

European-Non Finnish (NFE)

AF:

0.0000621

AC:

AN:

32194

Other (OTH)

AF:

0.00

AC:

AN:

778

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lynch syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over