rs3732183

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1661+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,606,350 control chromosomes in the GnomAD database, including 83,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.40 ( 14060 hom., cov: 32)

Exomes 𝑓: 0.30 ( 69924 hom. )

Consequence

MSH2
NM_000251.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:22

Conservation

PhyloP100: -0.868

Publications

40 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: ClinGen, Orphanet, G2P
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: 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: G2P, Labcorp Genetics (formerly Invitae)
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=-0.85).

BP6

Variant 2-47466820-G-A is Benign according to our data. Variant chr2-47466820-G-A is described in ClinVar as Benign. ClinVar VariationId is 36567.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.62 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	UniProt
MSH2	NM_000251.3	MANE Select	c.1661+12G>A	intron	N/A	NP_000242.1	P43246-1
MSH2	NM_001406674.1		c.1661+12G>A	intron	N/A	NP_001393603.1
MSH2	NM_001406631.1		c.1661+12G>A	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.1661+12G>A	intron	N/A	ENSP00000233146.2	P43246-1
MSH2	ENST00000406134.5	TSL:1	c.1661+12G>A	intron	N/A	ENSP00000384199.1	E9PHA6
MSH2	ENST00000918107.1		c.1712+12G>A	intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes

AF:

0.399

AC:

60625

AN:

151858

Hom.:

14041

Cov.:

show subpopulations

Gnomad AFR

AF:

0.623

Gnomad AMI

AF:

0.234

Gnomad AMR

AF:

0.340

Gnomad ASJ

AF:

0.227

Gnomad EAS

AF:

0.640

Gnomad SAS

AF:

0.342

Gnomad FIN

AF:

0.388

Gnomad MID

AF:

0.226

Gnomad NFE

AF:

0.277

Gnomad OTH

AF:

0.358

GnomAD2 exomes

AF:

0.343

AC:

85978

AN:

250680

AF XY:

0.334

show subpopulations

Gnomad AFR exome

AF:

0.628

Gnomad AMR exome

AF:

0.295

Gnomad ASJ exome

AF:

0.231

Gnomad EAS exome

AF:

0.657

Gnomad FIN exome

AF:

0.390

Gnomad NFE exome

AF:

0.274

Gnomad OTH exome

AF:

0.304

GnomAD4 exome

AF:

0.298

AC:

433217

AN:

1454372

Hom.:

69924

Cov.:

AF XY:

0.297

AC XY:

215255

AN XY:

724012

show subpopulations

African (AFR)

AF:

0.630

AC:

20938

AN:

33252

American (AMR)

AF:

0.300

AC:

13410

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

6145

AN:

26088

East Asian (EAS)

AF:

0.603

AC:

23858

AN:

39574

South Asian (SAS)

AF:

0.324

AC:

27898

AN:

86044

European-Finnish (FIN)

AF:

0.391

AC:

20861

AN:

53394

Middle Eastern (MID)

AF:

0.251

AC:

1355

AN:

5402

European-Non Finnish (NFE)

AF:

0.270

AC:

299007

AN:

1105852

Other (OTH)

AF:

0.329

AC:

19745

AN:

60074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

13755

27510

41265

55020

68775

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10272

20544

30816

41088

51360

<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:

0.399

AC:

60693

AN:

151978

Hom.:

14060

Cov.:

AF XY:

0.402

AC XY:

29850

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.623

AC:

25804

AN:

41426

American (AMR)

AF:

0.340

AC:

5190

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.227

AC:

787

AN:

3472

East Asian (EAS)

AF:

0.639

AC:

3300

AN:

5168

South Asian (SAS)

AF:

0.342

AC:

1652

AN:

4824

European-Finnish (FIN)

AF:

0.388

AC:

4089

AN:

10542

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.277

AC:

18838

AN:

67950

Other (OTH)

AF:

0.357

AC:

755

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1676

3352

5027

6703

8379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<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:

0.320

Hom.:

7603

Bravo

AF:

0.404

Asia WGS

AF:

0.493

AC:

1713

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Lynch syndrome 1 (5)

Lynch syndrome (3)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Endometrial carcinoma (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.3

(source)

DANN

Benign

0.60

PhyloP100

-0.87

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over