Genetic Variant ENST00000406134.5: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:

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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

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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