chr2-47475097-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000251.3(MSH2):​c.1832T>G​(p.Val611Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MSH2
NM_000251.3 missense

Scores

9
5
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.42
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 6 ACMG points.

PM1
In a region_of_interest Interaction with EXO1 (size 70) in uniprot entity MSH2_HUMAN there are 24 pathogenic changes around while only 4 benign (86%) in NM_000251.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH2NM_000251.3 linkc.1832T>G p.Val611Gly missense_variant 12/16 ENST00000233146.7 NP_000242.1 P43246-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkc.1832T>G p.Val611Gly missense_variant 12/161 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2022MSH2: PM2, PM5:Supporting -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.36
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.81
D;.;.;.
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.092
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.83
T;D;D;D
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.92
D;D;D;D
MetaSVM
Uncertain
0.36
D
MutationAssessor
Pathogenic
3.8
H;.;.;.
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-3.3
D;D;.;D
REVEL
Pathogenic
0.79
Sift
Pathogenic
0.0
D;D;.;D
Sift4G
Pathogenic
0.0010
D;D;.;D
Polyphen
0.087
B;.;.;B
Vest4
0.63
MutPred
0.81
Gain of disorder (P = 0.0188);.;Gain of disorder (P = 0.0188);Gain of disorder (P = 0.0188);
MVP
0.96
MPC
0.0069
ClinPred
1.0
D
GERP RS
3.2
Varity_R
0.95
gMVP
0.79

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: chr2-47702236; API