Genetic Variant MSH2:c.2753-2636G>T (chr2-47658337-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001406631.1(MSH2):c.2753-2636G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 152,066 control chromosomes in the GnomAD database, including 39,910 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 0.72 ( 39910 hom., cov: 32)

Consequence

MSH2
NM_001406631.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.55

Publications

11 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:

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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=-1.05).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406631.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
MSH2	NM_001406631.1	c.2753-2636G>T	intron	N/A	NP_001393560.1
MSH2	NM_001406632.1	c.2845+1045G>T	intron	N/A	NP_001393561.1
MSH2	NM_001406633.1	c.2753-2636G>T	intron	N/A	NP_001393562.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000644092.1		n.*1419+1045G>T		intron	N/A	ENSP00000496351.1	A0A2R8Y7S8
	MSH2	ENST00000645339.1		n.*172+1045G>T		intron	N/A	ENSP00000496441.1	A0A2R8YFH0

Frequencies

GnomAD3 genomes

AF:

0.716

AC:

108805

AN:

151948

Hom.:

39850

Cov.:

show subpopulations

Gnomad AFR

AF:

0.882

Gnomad AMI

AF:

0.697

Gnomad AMR

AF:

0.636

Gnomad ASJ

AF:

0.593

Gnomad EAS

AF:

0.637

Gnomad SAS

AF:

0.678

Gnomad FIN

AF:

0.764

Gnomad MID

AF:

0.658

Gnomad NFE

AF:

0.642

Gnomad OTH

AF:

0.686

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

GnomAD4 genome

AF:

0.716

AC:

108918

AN:

152066

Hom.:

39910

Cov.:

AF XY:

0.718

AC XY:

53367

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.882

AC:

36620

AN:

41498

American (AMR)

AF:

0.637

AC:

9730

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.593

AC:

2057

AN:

3468

East Asian (EAS)

AF:

0.638

AC:

3287

AN:

5154

South Asian (SAS)

AF:

0.679

AC:

3268

AN:

4816

European-Finnish (FIN)

AF:

0.764

AC:

8089

AN:

10592

Middle Eastern (MID)

AF:

0.667

AC:

196

AN:

294

European-Non Finnish (NFE)

AF:

0.642

AC:

43606

AN:

67956

Other (OTH)

AF:

0.680

AC:

1429

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1480

2959

4439

5918

7398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

822

1644

2466

3288

4110

<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:

0.663

Hom.:

86086

Bravo

AF:

0.716

Asia WGS

AF:

0.635

AC:

2210

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.078

(source)

DANN

Benign

0.50

PhyloP100

-1.6

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