2-47466649-A-T

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.1511-9A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,612,776 control chromosomes in the GnomAD database, including 12,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.088 ( 862 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11363 hom. )

Consequence

MSH2
NM_000251.3 intron

Scores

Splicing: ADA: 0.0001214

Clinical Significance

Benign reviewed by expert panel B:24

Conservation

PhyloP100: 0.684

Publications

21 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=-0.8).

BP6

Variant 2-47466649-A-T is Benign according to our data. Variant chr2-47466649-A-T is described in ClinVar as Benign. ClinVar VariationId is 36566.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 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.1511-9A>T	intron	N/A	NP_000242.1	P43246-1
MSH2	NM_001406674.1		c.1511-9A>T	intron	N/A	NP_001393603.1
MSH2	NM_001406631.1		c.1511-9A>T	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.1511-9A>T	intron	N/A	ENSP00000233146.2	P43246-1
MSH2	ENST00000406134.5	TSL:1	c.1511-9A>T	intron	N/A	ENSP00000384199.1	E9PHA6
MSH2	ENST00000918107.1		c.1562-9A>T	intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes

AF:

0.0882

AC:

13409

AN:

152108

Hom.:

862

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0221

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.0771

Gnomad ASJ

AF:

0.0464

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0225

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.0942

GnomAD2 exomes

AF:

0.0872

AC:

21885

AN:

250964

AF XY:

0.0869

show subpopulations

Gnomad AFR exome

AF:

0.0197

Gnomad AMR exome

AF:

0.0520

Gnomad ASJ exome

AF:

0.0503

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.151

Gnomad NFE exome

AF:

0.129

Gnomad OTH exome

AF:

0.0896

GnomAD4 exome

AF:

0.116

AC:

169095

AN:

1460550

Hom.:

11363

Cov.:

AF XY:

0.114

AC XY:

82633

AN XY:

726652

show subpopulations

African (AFR)

AF:

0.0171

AC:

572

AN:

33464

American (AMR)

AF:

0.0550

AC:

2459

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0539

AC:

1409

AN:

26124

East Asian (EAS)

AF:

0.000277

AC:

AN:

39658

South Asian (SAS)

AF:

0.0265

AC:

2287

AN:

86208

European-Finnish (FIN)

AF:

0.148

AC:

7887

AN:

53410

Middle Eastern (MID)

AF:

0.0213

AC:

123

AN:

5766

European-Non Finnish (NFE)

AF:

0.134

AC:

148355

AN:

1110878

Other (OTH)

AF:

0.0993

AC:

5992

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

6834

13667

20501

27334

34168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5088

10176

15264

20352

25440

<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:

0.0881

AC:

13411

AN:

152226

Hom.:

862

Cov.:

AF XY:

0.0862

AC XY:

6413

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0220

AC:

914

AN:

41538

American (AMR)

AF:

0.0770

AC:

1178

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0464

AC:

161

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5188

South Asian (SAS)

AF:

0.0230

AC:

111

AN:

4830

European-Finnish (FIN)

AF:

0.153

AC:

1624

AN:

10584

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.133

AC:

9053

AN:

67994

Other (OTH)

AF:

0.0932

AC:

197

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

616

1232

1847

2463

3079

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<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:

0.116

Hom.:

385

Bravo

AF:

0.0799

Asia WGS

AF:

0.0150

AC:

AN:

3476

EpiCase

AF:

0.112

EpiControl

AF:

0.115

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lynch syndrome 1 (7)

not specified (7)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Lynch syndrome (2)

Carcinoma of colon (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.2

(source)

DANN

Benign

0.68

PhyloP100

0.68

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.050

Splicevardb

1.0

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