GeneBe

2-47414399-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000251.3(MSH2):​c.923G>T​(p.Arg308Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R308T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 26)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

MSH2
NM_000251.3 missense

Scores

8
10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.38

Publications

0 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

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 20 benign, 38 uncertain in NM_000251.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.827

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.923G>Tp.Arg308Ile
missense
Exon 5 of 16NP_000242.1P43246-1
MSH2
NM_001406674.1
c.923G>Tp.Arg308Ile
missense
Exon 5 of 18NP_001393603.1
MSH2
NM_001406631.1
c.923G>Tp.Arg308Ile
missense
Exon 5 of 18NP_001393560.1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
MSH2
ENST00000233146.7
TSL:1 MANE Select
c.923G>Tp.Arg308Ile
missense
Exon 5 of 16ENSP00000233146.2P43246-1
MSH2
ENST00000406134.5
TSL:1
c.923G>Tp.Arg308Ile
missense
Exon 5 of 16ENSP00000384199.1E9PHA6
MSH2
ENST00000918107.1
c.974G>Tp.Arg325Ile
missense
Exon 6 of 17ENSP00000588166.1

Frequencies

GnomAD3 genomes
Cov.:
26
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1072424
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
539982
African (AFR)
AF:
0.00
AC:
0
AN:
25038
American (AMR)
AF:
0.00
AC:
0
AN:
38480
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
18542
East Asian (EAS)
AF:
0.00
AC:
0
AN:
25402
South Asian (SAS)
AF:
0.00
AC:
0
AN:
77220
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
41658
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3662
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
800200
Other (OTH)
AF:
0.00
AC:
0
AN:
42222
GnomAD4 genome
Cov.:
26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.18
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.82
D
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.83
D
MetaSVM
Uncertain
0.75
D
MutationAssessor
Uncertain
2.8
M
PhyloP100
4.4
PrimateAI
Uncertain
0.49
T
PROVEAN
Pathogenic
-5.3
D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0080
D
Polyphen
0.73
P
Vest4
0.68
MutPred
0.76
Gain of stability (P = 0.0159)
MVP
0.94
MPC
0.021
ClinPred
0.99
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.38
gMVP
0.35
Mutation Taster
=54/46
polymorphism

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: rs1553352545; hg19: chr2-47641538; API