chr2-47403074-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001258281.1(MSH2):c.-132T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 985,838 control chromosomes in the GnomAD database, including 8,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.10 ( 1088 hom., cov: 33)

Exomes 𝑓: 0.13 ( 7239 hom. )

Consequence

MSH2
NM_001258281.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign reviewed by expert panel B:12

Conservation

PhyloP100: 1.90

Publications

46 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 2-47403074-T-C is Benign according to our data. Variant chr2-47403074-T-C is described in ClinVar as Benign. ClinVar VariationId is 90485.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258281.1. 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_001258281.1		c.-132T>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001245210.1	P43246-2
MSH2	NM_001258281.1		c.-132T>C	5_prime_UTR	Exon 1 of 17	NP_001245210.1	P43246-2
MSH2	NM_000251.3	MANE Select	c.-118T>C	upstream_gene	N/A	NP_000242.1	P43246-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MSH2	ENST00000543555.6	TSL:2	c.-132T>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000442697.1	P43246-2
MSH2	ENST00000543555.6	TSL:2	c.-132T>C	5_prime_UTR	Exon 1 of 17	ENSP00000442697.1	P43246-2
MSH2	ENST00000233146.7	TSL:1 MANE Select	c.-118T>C	upstream_gene	N/A	ENSP00000233146.2	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15784

AN:

151944

Hom.:

1090

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0265

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.142

Gnomad ASJ

AF:

0.0599

Gnomad EAS

AF:

0.181

Gnomad SAS

AF:

0.0632

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.106

GnomAD4 exome

AF:

0.126

AC:

105018

AN:

833776

Hom.:

7239

Cov.:

AF XY:

0.123

AC XY:

53236

AN XY:

431420

show subpopulations

African (AFR)

AF:

0.0217

AC:

455

AN:

20920

American (AMR)

AF:

0.148

AC:

5192

AN:

35004

Ashkenazi Jewish (ASJ)

AF:

0.0643

AC:

1397

AN:

21726

East Asian (EAS)

AF:

0.161

AC:

5333

AN:

33206

South Asian (SAS)

AF:

0.0556

AC:

3761

AN:

67588

European-Finnish (FIN)

AF:

0.147

AC:

4921

AN:

33518

Middle Eastern (MID)

AF:

0.0398

AC:

121

AN:

3044

European-Non Finnish (NFE)

AF:

0.137

AC:

79199

AN:

579004

Other (OTH)

AF:

0.117

AC:

4639

AN:

39766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

5245

10489

15734

20978

26223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2008

4016

6024

8032

10040

<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:

0.104

AC:

15783

AN:

152062

Hom.:

1088

Cov.:

AF XY:

0.105

AC XY:

7819

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0264

AC:

1096

AN:

41528

American (AMR)

AF:

0.143

AC:

2177

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.0599

AC:

208

AN:

3472

East Asian (EAS)

AF:

0.180

AC:

923

AN:

5134

South Asian (SAS)

AF:

0.0639

AC:

307

AN:

4806

European-Finnish (FIN)

AF:

0.153

AC:

1620

AN:

10568

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.133

AC:

9030

AN:

67974

Other (OTH)

AF:

0.105

AC:

222

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

733

1466

2198

2931

3664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<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:

0.112

Hom.:

324

Bravo

AF:

0.101

Asia WGS

AF:

0.116

AC:

404

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lynch syndrome 1 (3)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Lynch syndrome (2)

Hereditary nonpolyposis colorectal neoplasms (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

1.9

PromoterAI

-0.27

Neutral

(source)

Mutation Taster

=300/0

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