2-47410283-A-G

Variant summary

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

The NM_000251.3(MSH2):​c.556A>G​(p.Asn186Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

6
11
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.25
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a helix (size 9) in uniprot entity MSH2_HUMAN there are 4 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, 0.758

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH2NM_000251.3 linkc.556A>G p.Asn186Asp missense_variant Exon 3 of 16 ENST00000233146.7 NP_000242.1 P43246-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkc.556A>G p.Asn186Asp missense_variant Exon 3 of 16 1 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251480
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461878
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jun 05, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The MSH2 c.556A>G (p.Asn186Asp) variant has not been reported in individuals with MSH2-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/251480 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1
May 31, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces asparagine with aspartic acid at codon 186 of the MSH2 protein (p.Asn186Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs766497093, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related conditions. 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. In 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.86
D;D;.;.;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D;D;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.76
D;D;D;D;D
MetaSVM
Uncertain
0.74
D
MutationAssessor
Pathogenic
3.0
M;.;.;.;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-4.4
D;D;D;.;D
REVEL
Pathogenic
0.68
Sift
Uncertain
0.028
D;T;D;.;D
Sift4G
Benign
0.087
T;T;T;.;T
Polyphen
0.87
P;.;.;.;D
Vest4
0.83
MutPred
0.46
Loss of catalytic residue at N186 (P = 0.0958);.;.;Loss of catalytic residue at N186 (P = 0.0958);Loss of catalytic residue at N186 (P = 0.0958);
MVP
0.95
MPC
0.028
ClinPred
0.99
D
GERP RS
4.6
Varity_R
0.84
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

LitVar

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

Other links and lift over

dbSNP: rs766497093; hg19: chr2-47637422; API