Genetic Variant MSH2:c.2634+5664T>G (chr2-47486535-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000406134.5(MSH2):c.2634+5664T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0327 in 152,278 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.033 ( 133 hom., cov: 33)

Consequence

MSH2
ENST00000406134.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.497

Publications

4 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
MSH2	NM_001406674.1 link	c.2634+5664T>G	intron_variant	Intron 15 of 17	NP_001393603.1
MSH2	NM_001406631.1 link	c.2634+5664T>G	intron_variant	Intron 15 of 17	NP_001393560.1
MSH2	NM_001406632.1 link	c.2634+5664T>G	intron_variant	Intron 15 of 18	NP_001393561.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
MSH2	ENST00000406134.5 link	c.2634+5664T>G	intron_variant	Intron 15 of 15	1	ENSP00000384199.1	E9PHA6
MSH2	ENST00000645506.1 link	c.2634+5664T>G	intron_variant	Intron 15 of 16		ENSP00000495455.1	A0A2R8Y6P0
MSH2	ENST00000644092.1 link	n.*934+5664T>G	intron_variant	Intron 15 of 19		ENSP00000496351.1	A0A2R8Y7S8

Frequencies

GnomAD3 genomes

AF:

0.0326

AC:

4968

AN:

152160

Hom.:

132

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0652

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.0184

Gnomad ASJ

AF:

0.0366

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0344

Gnomad FIN

AF:

0.0147

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0212

Gnomad OTH

AF:

0.0335

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0327

AC:

4972

AN:

152278

Hom.:

133

Cov.:

AF XY:

0.0313

AC XY:

2332

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0652

AC:

2710

AN:

41556

American (AMR)

AF:

0.0183

AC:

280

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

127

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.0342

AC:

165

AN:

4826

European-Finnish (FIN)

AF:

0.0147

AC:

156

AN:

10596

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0212

AC:

1440

AN:

68026

Other (OTH)

AF:

0.0331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

239

478

717

956

1195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0331

Hom.:

Bravo

AF:

0.0335

Asia WGS

AF:

0.0240

AC:

AN:

3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.50

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over