chr2-47463014-CTTTG-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000251.3(MSH2):c.1387-14_1387-11delTGTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,612,850 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 4 hom. )

Consequence

MSH2
NM_000251.3 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 0.911

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: 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 -9 ACMG points.

BP6

Variant 2-47463014-CTTTG-C is Benign according to our data. Variant chr2-47463014-CTTTG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 418315.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000344 (502/1460630) while in subpopulation SAS AF = 0.00538 (464/86206). AF 95% confidence interval is 0.00498. There are 4 homozygotes in GnomAdExome4. There are 387 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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.1387-14_1387-11delTGTT	intron	N/A	NP_000242.1	P43246-1
MSH2	NM_001406674.1		c.1387-14_1387-11delTGTT	intron	N/A	NP_001393603.1
MSH2	NM_001406631.1		c.1387-14_1387-11delTGTT	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.1387-16_1387-13delTTTG	intron	N/A	ENSP00000233146.2	P43246-1
MSH2	ENST00000406134.5	TSL:1	c.1387-16_1387-13delTTTG	intron	N/A	ENSP00000384199.1	E9PHA6
MSH2	ENST00000918107.1		c.1438-16_1438-13delTTTG	intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152102

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:

0.00476

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000689

AC:

173

AN:

251094

AF XY:

0.00101

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:

0.0000176

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000344

AC:

502

AN:

1460630

Hom.:

AF XY:

0.000533

AC XY:

387

AN XY:

726658

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00538

AC:

464

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5482

European-Non Finnish (NFE)

AF:

0.00000990

AC:

AN:

1111368

Other (OTH)

AF:

0.000431

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

110

137

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:

0.000151

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41538

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00476

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (3)

not provided (3)

not specified (2)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome (1)

Lynch syndrome 1 (1)

Muir-Torré syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.91

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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