2-47403411-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000251.3(MSH2):c.211+9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,587,578 control chromosomes in the GnomAD database, including 157,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.53 ( 23530 hom., cov: 34)

Exomes 𝑓: 0.42 ( 133998 hom. )

Consequence

MSH2
NM_000251.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:24

Conservation

PhyloP100: -3.39

Publications

53 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 2-47403411-C-G is Benign according to our data. Variant chr2-47403411-C-G is described in ClinVar as Benign. ClinVar VariationId is 36573.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MSH2	NM_000251.3	MANE Select	c.211+9C>G	intron	N/A	NP_000242.1
MSH2	NM_001406674.1		c.211+9C>G	intron	N/A	NP_001393603.1
MSH2	NM_001406631.1		c.211+9C>G	intron	N/A	NP_001393560.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MSH2	ENST00000233146.7	TSL:1 MANE Select	c.211+9C>G	intron	N/A	ENSP00000233146.2
MSH2	ENST00000406134.5	TSL:1	c.211+9C>G	intron	N/A	ENSP00000384199.1
MSH2	ENST00000645506.1		c.211+9C>G	intron	N/A	ENSP00000495455.1

Frequencies

GnomAD3 genomes

AF:

0.530

AC:

80592

AN:

151992

Hom.:

23493

Cov.:

show subpopulations

Gnomad AFR

AF:

0.757

Gnomad AMI

AF:

0.343

Gnomad AMR

AF:

0.471

Gnomad ASJ

AF:

0.336

Gnomad EAS

AF:

0.803

Gnomad SAS

AF:

0.473

Gnomad FIN

AF:

0.576

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.396

Gnomad OTH

AF:

0.488

GnomAD2 exomes

AF:

0.473

AC:

101041

AN:

213394

AF XY:

0.462

show subpopulations

Gnomad AFR exome

AF:

0.766

Gnomad AMR exome

AF:

0.453

Gnomad ASJ exome

AF:

0.335

Gnomad EAS exome

AF:

0.815

Gnomad FIN exome

AF:

0.575

Gnomad NFE exome

AF:

0.386

Gnomad OTH exome

AF:

0.423

GnomAD4 exome

AF:

0.421

AC:

604488

AN:

1435464

Hom.:

133998

Cov.:

AF XY:

0.420

AC XY:

298308

AN XY:

710378

show subpopulations

African (AFR)

AF:

0.768

AC:

25467

AN:

33144

American (AMR)

AF:

0.452

AC:

18749

AN:

41440

Ashkenazi Jewish (ASJ)

AF:

0.337

AC:

8620

AN:

25564

East Asian (EAS)

AF:

0.775

AC:

30072

AN:

38794

South Asian (SAS)

AF:

0.454

AC:

37938

AN:

83486

European-Finnish (FIN)

AF:

0.570

AC:

28822

AN:

50530

Middle Eastern (MID)

AF:

0.343

AC:

1620

AN:

4722

European-Non Finnish (NFE)

AF:

0.388

AC:

426530

AN:

1098582

Other (OTH)

AF:

0.450

AC:

26670

AN:

59202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

17104

34207

51311

68414

85518

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13650

27300

40950

54600

68250

<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:

0.530

AC:

80679

AN:

152114

Hom.:

23530

Cov.:

AF XY:

0.538

AC XY:

39972

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.757

AC:

31453

AN:

41528

American (AMR)

AF:

0.471

AC:

7204

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.336

AC:

1167

AN:

3472

East Asian (EAS)

AF:

0.802

AC:

4127

AN:

5148

South Asian (SAS)

AF:

0.473

AC:

2282

AN:

4824

European-Finnish (FIN)

AF:

0.576

AC:

6091

AN:

10566

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.396

AC:

26919

AN:

67972

Other (OTH)

AF:

0.486

AC:

1025

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1618

3236

4853

6471

8089

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

668

1336

2004

2672

3340

<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:

0.371

Hom.:

3171

Bravo

AF:

0.531

Asia WGS

AF:

0.637

AC:

2216

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Lynch syndrome 1 (6)

Hereditary cancer-predisposing syndrome (3)

Lynch syndrome (3)

not provided (3)

Carcinoma of colon (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.060

(source)

DANN

Benign

0.52

PhyloP100

-3.4

PromoterAI

-0.17

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over