chr2-47475097-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_ModerateBP6_Moderate

The NM_000251.3(MSH2):​c.1832T>C​(p.Val611Ala) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MSH2
NM_000251.3 missense

Scores

4
15

Clinical Significance

Likely benign criteria provided, single submitter B: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 Uncertain_significance. Variant got 0 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;
BP4
Computational evidence support a benign effect (MetaRNN=0.2320287).
BP6
Variant 2-47475097-T-C is Benign according to our data. Variant chr2-47475097-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1780989.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH2NM_000251.3 linkc.1832T>C p.Val611Ala 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>C p.Val611Ala 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: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 05, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Uncertain
0.096
D
BayesDel_noAF
Benign
-0.10
CADD
Benign
13
DANN
Benign
0.90
DEOGEN2
Benign
0.39
T;.;.;.
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.48
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.73
T;T;T;T
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.23
T;T;T;T
MetaSVM
Benign
-0.53
T
MutationAssessor
Benign
0.48
N;.;.;.
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.020
N;N;.;N
REVEL
Uncertain
0.35
Sift
Benign
0.67
T;T;.;T
Sift4G
Benign
0.66
T;T;.;T
Polyphen
0.0
B;.;.;B
Vest4
0.45
MutPred
0.76
Gain of disorder (P = 0.0657);.;Gain of disorder (P = 0.0657);Gain of disorder (P = 0.0657);
MVP
0.77
MPC
0.0061
ClinPred
0.11
T
GERP RS
3.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.081
gMVP
0.68

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