rs1553361274

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

Scores

11
7
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.71
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]

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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
MSH2NM_000251.3 linkuse as main transcriptc.1355A>T p.Glu452Val missense_variant 8/16 ENST00000233146.7 NP_000242.1 P43246-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.1355A>T p.Glu452Val missense_variant 8/161 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
29
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 submitterclinical testingAmbry GeneticsFeb 19, 2021The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
35
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.84
D;.;.;.
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.87
D;T;D;D
M_CAP
Uncertain
0.29
D
MetaRNN
Pathogenic
0.87
D;D;D;D
MetaSVM
Pathogenic
0.88
D
MutationAssessor
Pathogenic
3.0
M;.;.;.
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-6.2
D;D;.;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0010
D;D;.;D
Sift4G
Uncertain
0.0070
D;D;.;D
Polyphen
0.60
P;.;.;D
Vest4
0.88
MutPred
0.57
Loss of disorder (P = 0.0294);.;Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);
MVP
0.97
MPC
0.0081
ClinPred
0.99
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.4
Varity_R
0.90
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.98
Position offset: -2
DS_DL_spliceai
0.38
Position offset: 31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553361274; hg19: chr2-47672765; API