2-47478353-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1PM2PP3_StrongBP6

The NM_000251.3(MSH2):​c.2292G>C​(p.Trp764Cys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

MSH2
NM_000251.3 missense

Scores

16
2
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 9.55
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 7 ACMG points.

PM1
In a helix (size 16) in uniprot entity MSH2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000251.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.95
BP6
Variant 2-47478353-G-C is Benign according to our data. Variant chr2-47478353-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90950.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH2NM_000251.3 linkc.2292G>C p.Trp764Cys missense_variant 14/16 ENST00000233146.7 NP_000242.1 P43246-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkc.2292G>C p.Trp764Cys missense_variant 14/161 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

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

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 08, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 90950). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18987546, 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 764 of the MSH2 protein (p.Trp764Cys). -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 23, 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
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.86
D;.;.;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.95
D;D;D;D
MetaSVM
Uncertain
0.77
D
MutationAssessor
Pathogenic
3.2
M;.;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-12
D;D;.;D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D;D;.;D
Sift4G
Pathogenic
0.0
D;D;.;D
Polyphen
1.0
D;.;.;D
Vest4
0.94
MutPred
0.77
Gain of glycosylation at S767 (P = 0.2749);.;Gain of glycosylation at S767 (P = 0.2749);Gain of glycosylation at S767 (P = 0.2749);
MVP
0.97
MPC
0.029
ClinPred
1.0
D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.95
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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: rs63751105; hg19: chr2-47705492; API