rs3764959

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.1759+107A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 680,402 control chromosomes in the GnomAD database, including 45,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene MSH2 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.41 ( 15525 hom., cov: 32)

Exomes 𝑓: 0.32 ( 30424 hom. )

Consequence

MSH2
NM_000251.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0160

Publications

10 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:

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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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 2-47471169-A-G is Benign according to our data. Variant chr2-47471169-A-G is described in ClinVar as Benign. ClinVar VariationId is 439907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 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.1759+107A>G	intron	N/A	NP_000242.1	P43246-1
MSH2	NM_001406674.1		c.1759+107A>G	intron	N/A	NP_001393603.1
MSH2	NM_001406631.1		c.1759+107A>G	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.1759+107A>G	intron	N/A	ENSP00000233146.2	P43246-1
MSH2	ENST00000406134.5	TSL:1	c.1759+107A>G	intron	N/A	ENSP00000384199.1	E9PHA6
MSH2	ENST00000918107.1		c.1810+107A>G	intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes

AF:

0.414

AC:

62877

AN:

151936

Hom.:

15497

Cov.:

show subpopulations

Gnomad AFR

AF:

0.673

Gnomad AMI

AF:

0.234

Gnomad AMR

AF:

0.346

Gnomad ASJ

AF:

0.227

Gnomad EAS

AF:

0.641

Gnomad SAS

AF:

0.342

Gnomad FIN

AF:

0.388

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.277

Gnomad OTH

AF:

0.371

GnomAD4 exome

AF:

0.322

AC:

170205

AN:

528348

Hom.:

30424

AF XY:

0.318

AC XY:

90410

AN XY:

284408

show subpopulations

African (AFR)

AF:

0.671

AC:

9877

AN:

14722

American (AMR)

AF:

0.310

AC:

9906

AN:

31988

Ashkenazi Jewish (ASJ)

AF:

0.233

AC:

4373

AN:

18752

East Asian (EAS)

AF:

0.593

AC:

18014

AN:

30364

South Asian (SAS)

AF:

0.320

AC:

19294

AN:

60262

European-Finnish (FIN)

AF:

0.386

AC:

16991

AN:

43994

Middle Eastern (MID)

AF:

0.246

AC:

574

AN:

2330

European-Non Finnish (NFE)

AF:

0.274

AC:

81566

AN:

297718

Other (OTH)

AF:

0.341

AC:

9610

AN:

28218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

5508

11015

16523

22030

27538

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

640

1280

1920

2560

3200

<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:

0.414

AC:

62957

AN:

152054

Hom.:

15525

Cov.:

AF XY:

0.416

AC XY:

30941

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.674

AC:

27917

AN:

41438

American (AMR)

AF:

0.346

AC:

5282

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.227

AC:

787

AN:

3472

East Asian (EAS)

AF:

0.640

AC:

3309

AN:

5174

South Asian (SAS)

AF:

0.342

AC:

1650

AN:

4820

European-Finnish (FIN)

AF:

0.388

AC:

4096

AN:

10570

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.277

AC:

18854

AN:

67980

Other (OTH)

AF:

0.370

AC:

781

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1673

3346

5019

6692

8365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

548

1096

1644

2192

2740

<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:

0.330

Hom.:

3363

Bravo

AF:

0.421

Asia WGS

AF:

0.496

AC:

1722

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.59

(source)

DANN

Benign

0.41

PhyloP100

-0.016

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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