GeneBe

NM_000251.3:c.204delG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000251.3(MSH2):​c.204delG​(p.Pro69ArgfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. G68G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

MSH2
NM_000251.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 0.0860

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: 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-47403391-TG-T is Pathogenic according to our data. Variant chr2-47403391-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 90871.Status of the report is reviewed_by_expert_panel, 3 stars.

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

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
MSH2
NM_000251.3
MANE Select
c.204delGp.Pro69ArgfsTer15
frameshift
Exon 1 of 16NP_000242.1P43246-1
MSH2
NM_001406674.1
c.204delGp.Pro69ArgfsTer15
frameshift
Exon 1 of 18NP_001393603.1
MSH2
NM_001406631.1
c.204delGp.Pro69ArgfsTer15
frameshift
Exon 1 of 18NP_001393560.1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
MSH2
ENST00000233146.7
TSL:1 MANE Select
c.204delGp.Pro69ArgfsTer15
frameshift
Exon 1 of 16ENSP00000233146.2P43246-1
MSH2
ENST00000406134.5
TSL:1
c.204delGp.Pro69ArgfsTer15
frameshift
Exon 1 of 16ENSP00000384199.1E9PHA6
MSH2
ENST00000918107.1
c.204delGp.Pro69ArgfsTer15
frameshift
Exon 1 of 17ENSP00000588166.1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1448782
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
718870
African (AFR)
AF:
0.00
AC:
0
AN:
33300
American (AMR)
AF:
0.00
AC:
0
AN:
43526
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25760
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39230
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84682
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51590
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5136
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1105796
Other (OTH)
AF:
0.00
AC:
0
AN:
59762
GnomAD4 genome
Cov.:
33

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar
Pathogenic
VUS
Benign
Condition
2
-
-
Lynch syndrome (2)
1
-
-
Breast carcinoma (1)
1
-
-
Hereditary cancer-predisposing syndrome (1)
1
-
-
Hereditary nonpolyposis colorectal neoplasms (1)
1
-
-
Lynch syndrome 1 (1)
1
-
-
not provided (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.086
Mutation Taster
=1/199
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63750199; hg19: chr2-47630530; API