chr2-47463272-T-C

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.1510+118T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,231,666 control chromosomes in the GnomAD database, including 84,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 18402 hom., cov: 32)

Exomes 𝑓: 0.33 ( 66504 hom. )

Consequence

MSH2
NM_000251.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.573

Publications

7 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=-0.96).

BP6

Variant 2-47463272-T-C is Benign according to our data. Variant chr2-47463272-T-C is described in ClinVar as Benign. ClinVar VariationId is 676474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.1510+118T>C		intron_variant	Intron 9 of 15	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.1510+118T>C		intron_variant	Intron 9 of 15	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.455

AC:

68897

AN:

151428

Hom.:

18356

Cov.:

show subpopulations

Gnomad AFR

AF:

0.737

Gnomad AMI

AF:

0.280

Gnomad AMR

AF:

0.369

Gnomad ASJ

AF:

0.243

Gnomad EAS

AF:

0.645

Gnomad SAS

AF:

0.352

Gnomad FIN

AF:

0.445

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.313

Gnomad OTH

AF:

0.413

GnomAD4 exome

AF:

0.334

AC:

360352

AN:

1080118

Hom.:

66504

AF XY:

0.332

AC XY:

182426

AN XY:

549868

show subpopulations

African (AFR)

AF:

0.755

AC:

18307

AN:

24242

American (AMR)

AF:

0.331

AC:

12436

AN:

37604

Ashkenazi Jewish (ASJ)

AF:

0.251

AC:

5535

AN:

22090

East Asian (EAS)

AF:

0.607

AC:

22181

AN:

36548

South Asian (SAS)

AF:

0.334

AC:

24170

AN:

72268

European-Finnish (FIN)

AF:

0.447

AC:

22304

AN:

49912

Middle Eastern (MID)

AF:

0.276

AC:

1229

AN:

4456

European-Non Finnish (NFE)

AF:

0.301

AC:

236869

AN:

786124

Other (OTH)

AF:

0.370

AC:

17321

AN:

46874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

11084

22169

33253

44338

55422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6902

13804

20706

27608

34510

<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:

0.455

AC:

68999

AN:

151548

Hom.:

18402

Cov.:

AF XY:

0.457

AC XY:

33845

AN XY:

74044

show subpopulations

African (AFR)

AF:

0.738

AC:

30434

AN:

41260

American (AMR)

AF:

0.369

AC:

5630

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.243

AC:

840

AN:

3458

East Asian (EAS)

AF:

0.643

AC:

3288

AN:

5110

South Asian (SAS)

AF:

0.352

AC:

1693

AN:

4812

European-Finnish (FIN)

AF:

0.445

AC:

4689

AN:

10538

Middle Eastern (MID)

AF:

0.282

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.313

AC:

21225

AN:

67820

Other (OTH)

AF:

0.411

AC:

866

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1634

3268

4903

6537

8171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

584

1168

1752

2336

2920

<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:

0.514

Hom.:

6151

Bravo

AF:

0.463

Asia WGS

AF:

0.514

AC:

1787

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 20, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

2.0

(source)

DANN

Benign

0.53

PhyloP100

-0.57

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over