rs1553361274
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate
The NM_000251.3(MSH2):c.1355A>T(p.Glu452Val) 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. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
MSH2
NM_000251.3 missense
NM_000251.3 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 6.71
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a helix (size 18) in uniprot entity MSH2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000251.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.866
PP5
Variant 2-47445626-A-T is Pathogenic according to our data. Variant chr2-47445626-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 483677.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47445626-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1355A>T | p.Glu452Val | missense_variant | 8/16 | ENST00000233146.7 | NP_000242.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1355A>T | p.Glu452Val | missense_variant | 8/16 | 1 | NM_000251.3 | ENSP00000233146.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 19, 2021 | The p.E452V variant (also known as c.1355A>T), located in coding exon 8 of the MSH2 gene, results from an A to T substitution at nucleotide position 1355. The glutamic acid at codon 452 is replaced by valine, an amino acid with dissimilar properties. Splicing assays demonstrated that this variant results in the activation of the cryptic donor site led to a 33 bp in-frame deletion resulting in loss of the terminal 11 amino acids of exon 8 (Ambry internal data). This alteration has also been reported as a variant of uncertain significance in a 38 year old female with proximal colon cancer and a family history meeting Amsterdam criteria (Chubb D et al, J. Clin. Oncol. 2015 Feb; 33(5):426-32). This alteration is located in the MutS DNA binding domain of the MSH2 protein. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;T;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;D
REVEL
Pathogenic
Sift
Uncertain
D;D;.;D
Sift4G
Uncertain
D;D;.;D
Polyphen
P;.;.;D
Vest4
MutPred
Loss of disorder (P = 0.0294);.;Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -2
DS_DL_spliceai
Position offset: 31
Find out detailed SpliceAI scores and Pangolin per-transcript scores at