2-47408384-CTTT-CTTTTT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000251.3(MSH2):c.212-5_212-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★). The gene MSH2 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00066 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MSH2
NM_000251.3 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.95

Publications

1 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

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: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 2-47408384-C-CTT is Benign according to our data. Variant chr2-47408384-C-CTT is described in ClinVar as Likely_benign. ClinVar VariationId is 3772811.Status of the report is criteria_provided_single_submitter, 1 stars.

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.212-5_212-4dupTT	splice_region intron	N/A	NP_000242.1	P43246-1
MSH2	NM_001406674.1		c.212-5_212-4dupTT	splice_region intron	N/A	NP_001393603.1
MSH2	NM_001406631.1		c.212-5_212-4dupTT	splice_region 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.212-17_212-16insTT	intron	N/A	ENSP00000233146.2	P43246-1
MSH2	ENST00000406134.5	TSL:1	c.212-17_212-16insTT	intron	N/A	ENSP00000384199.1	E9PHA6
MSH2	ENST00000918107.1		c.212-17_212-16insTT	intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

144140

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000949

AC:

102

AN:

107442

AF XY:

0.00102

show subpopulations

Gnomad AFR exome

AF:

0.000142

Gnomad AMR exome

AF:

0.00120

Gnomad ASJ exome

AF:

0.000943

Gnomad EAS exome

AF:

0.000899

Gnomad FIN exome

AF:

0.000106

Gnomad NFE exome

AF:

0.000806

Gnomad OTH exome

AF:

0.00109

GnomAD4 exome

AF:

0.000658

AC:

785

AN:

1192788

Hom.:

Cov.:

AF XY:

0.000590

AC XY:

353

AN XY:

598288

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000721

AC:

AN:

27724

American (AMR)

AF:

0.000756

AC:

AN:

38348

Ashkenazi Jewish (ASJ)

AF:

0.000396

AC:

AN:

22720

East Asian (EAS)

AF:

0.000260

AC:

AN:

34670

South Asian (SAS)

AF:

0.000665

AC:

AN:

76650

European-Finnish (FIN)

AF:

0.000406

AC:

AN:

44382

Middle Eastern (MID)

AF:

0.000403

AC:

AN:

4960

European-Non Finnish (NFE)

AF:

0.000699

AC:

624

AN:

893032

Other (OTH)

AF:

0.000457

AC:

AN:

50302

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.242

Heterozygous variant carriers

125

250

374

499

624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

144140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69936

African (AFR)

AF:

0.00

AC:

AN:

39390

American (AMR)

AF:

0.00

AC:

AN:

14284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3370

East Asian (EAS)

AF:

0.00

AC:

AN:

4988

South Asian (SAS)

AF:

0.00

AC:

AN:

4526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65432

Other (OTH)

AF:

0.00

AC:

AN:

1950

Alfa

AF:

0.00127

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lynch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.9

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over