GeneBe

chr2-47403286-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000251.3(MSH2):​c.95C>A​(p.Thr32Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T32I) has been classified as Likely benign.

Frequency

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

Consequence

MSH2
NM_000251.3 missense

Scores

3
12
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.23

Publications

3 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: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

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.95C>Ap.Thr32Asn
missense
Exon 1 of 16NP_000242.1P43246-1
MSH2
NM_001406674.1
c.95C>Ap.Thr32Asn
missense
Exon 1 of 18NP_001393603.1
MSH2
NM_001406631.1
c.95C>Ap.Thr32Asn
missense
Exon 1 of 18NP_001393560.1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
MSH2
ENST00000233146.7
TSL:1 MANE Select
c.95C>Ap.Thr32Asn
missense
Exon 1 of 16ENSP00000233146.2P43246-1
MSH2
ENST00000406134.5
TSL:1
c.95C>Ap.Thr32Asn
missense
Exon 1 of 16ENSP00000384199.1E9PHA6
MSH2
ENST00000918107.1
c.95C>Ap.Thr32Asn
missense
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:
1448662
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
719506
African (AFR)
AF:
0.00
AC:
0
AN:
33406
American (AMR)
AF:
0.00
AC:
0
AN:
42022
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25708
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39224
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83738
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51358
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5594
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1107694
Other (OTH)
AF:
0.00
AC:
0
AN:
59918
GnomAD4 genome
Cov.:
33

ClinVar

ClinVar submissions
Significance:Uncertain significance
Revision:criteria provided, single submitter
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
1
-
Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Uncertain
25
DANN
Benign
0.92
DEOGEN2
Uncertain
0.58
D
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.50
D
MetaRNN
Uncertain
0.66
D
MetaSVM
Uncertain
0.48
D
MutationAssessor
Uncertain
2.1
M
PhyloP100
7.2
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-2.6
D
REVEL
Uncertain
0.54
Sift
Benign
0.60
T
Sift4G
Benign
0.28
T
Polyphen
0.60
P
Vest4
0.67
MutPred
0.46
Loss of phosphorylation at T32 (P = 0.0334)
MVP
0.88
MPC
0.028
ClinPred
0.99
D
GERP RS
5.6
PromoterAI
0.018
Neutral
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.1
Varity_R
0.82
gMVP
0.58
Mutation Taster
=35/65
disease causing

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: rs552361923; hg19: chr2-47630425; API