chr2-47482768-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000251.3(MSH2):c.2635-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,604,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

MSH2
NM_000251.3 intron

Scores

Splicing: ADA: 0.00002572

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -0.959

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-47482768-A-G is Benign according to our data. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.2635-11A>G		intron_variant	Intron 15 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.2635-11A>G		intron_variant	Intron 15 of 15	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

250058

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

154

AN:

1452038

Hom.:

Cov.:

AF XY:

0.0000857

AC XY:

AN XY:

723044

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33248

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.00

AC:

AN:

85762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.000138

AC:

152

AN:

1103580

Other (OTH)

AF:

0.0000333

AC:

AN:

60052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000262

AC:

AN:

152388

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74522

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41600

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Sep 18, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jan 04, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast

Uncertain:1

Oct 01, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome 1

Benign:1

Dec 16, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.56

(source)

DANN

Benign

0.66

PhyloP100

-0.96

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over