Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000644092.1(MSH2):n.-73G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000955 in 1,458,210 control chromosomes in the GnomAD database, including 26 homozygotes. 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 0.00057 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 26 hom. )

Consequence

MSH2
ENST00000644092.1 non_coding_transcript_exon

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.23

Publications

2 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 2-47403119-G-A is Benign according to our data. Variant chr2-47403119-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141079.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000571 (87/152380) while in subpopulation SAS AF = 0.0151 (73/4834). AF 95% confidence interval is 0.0123. There are 0 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 26 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000644092.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MSH2	NM_001258281.1		c.-87G>A	5_prime_UTR	Exon 1 of 17	NP_001245210.1
MSH2	NM_000251.3	MANE Select	c.-73G>A	upstream_gene	N/A	NP_000242.1
MSH2	NM_001406674.1		c.-73G>A	upstream_gene	N/A	NP_001393603.1

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
MSH2	ENST00000644092.1	n.-73G>A	non_coding_transcript_exon	Exon 1 of 20	ENSP00000496351.1
MSH2	ENST00000645339.1	n.-73G>A	non_coding_transcript_exon	Exon 1 of 19	ENSP00000496441.1
MSH2	ENST00000646415.1	n.-73G>A	non_coding_transcript_exon	Exon 1 of 18	ENSP00000495543.1

Frequencies

GnomAD3 genomes

AF:

0.000578

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0153

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000999

AC:

1305

AN:

1305830

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

895

AN XY:

648506

show subpopulations

African (AFR)

AF:

0.000100

AC:

AN:

29936

American (AMR)

AF:

0.0000843

AC:

AN:

35608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24700

East Asian (EAS)

AF:

0.0000282

AC:

AN:

35478

South Asian (SAS)

AF:

0.0149

AC:

1151

AN:

77396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36110

Middle Eastern (MID)

AF:

0.000921

AC:

AN:

4342

European-Non Finnish (NFE)

AF:

0.000101

AC:

102

AN:

1007102

Other (OTH)

AF:

0.000743

AC:

AN:

55158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

157

236

314

393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000571

AC:

AN:

152380

Hom.:

Cov.:

AF XY:

0.000859

AC XY:

AN XY:

74524

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41594

American (AMR)

AF:

0.000457

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0151

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

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: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000347

Hom.:

Bravo

AF:

0.000162

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Lynch syndrome 1 (1)

MSH2-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

1.2

PromoterAI

-0.092

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=297/3

polymorphism

(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

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

rs552303079

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over