rs1553365723

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The ENST00000233146.7(MSH2):​c.1415C>A​(p.Pro472His) variant causes a missense change involving the alteration of a conserved nucleotide. 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. P472A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MSH2
ENST00000233146.7 missense

Scores

11
7
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.41
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 Uncertain_significance. Variant got 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 7 benign, 16 uncertain in ENST00000233146.7
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH2NM_000251.3 linkuse as main transcriptc.1415C>A p.Pro472His missense_variant 9/16 ENST00000233146.7 NP_000242.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.1415C>A p.Pro472His missense_variant 9/161 NM_000251.3 ENSP00000233146 P1P43246-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D;.;.;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.83
D;D;D;D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Uncertain
2.7
M;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-6.3
D;D;.;D
REVEL
Pathogenic
0.82
Sift
Pathogenic
0.0
D;D;.;D
Sift4G
Pathogenic
0.0010
D;D;.;D
Polyphen
0.34
B;.;.;D
Vest4
0.58
MutPred
0.47
Loss of methylation at K471 (P = 0.0926);.;Loss of methylation at K471 (P = 0.0926);Loss of methylation at K471 (P = 0.0926);
MVP
0.84
MPC
0.032
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.91
gMVP
0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-47690198; API