2-47476408-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1PM1PM2PP3_StrongPP5_Moderate

The NM_000251.3(MSH2):​c.2047G>C​(p.Gly683Arg) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

Frequency

Genomes: not found (cov: 32)

Consequence

MSH2
NM_000251.3 missense

Scores

18
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.60
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 Pathogenic. Variant got 14 ACMG points.

PS1
Transcript NM_000251.3 (MSH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
PM1
In a helix (size 16) in uniprot entity MSH2_HUMAN there are 14 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, 0.981
PP5
Variant 2-47476408-G-C is Pathogenic according to our data. Variant chr2-47476408-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2673350.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 linkuse as main transcriptc.2047G>C p.Gly683Arg missense_variant 13/16 ENST00000233146.7 NP_000242.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.2047G>C p.Gly683Arg missense_variant 13/161 NM_000251.3 ENSP00000233146 P1P43246-1

Frequencies

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

ClinVar

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

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Aug 07, 2023This variant is considered pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.92
D;.;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Pathogenic
0.88
D
MutationAssessor
Pathogenic
3.7
H;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-7.7
D;D;.;D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D;.;D
Sift4G
Pathogenic
0.0
D;D;.;D
Polyphen
1.0
D;.;.;D
Vest4
0.99
MutPred
0.89
Gain of MoRF binding (P = 0.0244);.;Gain of MoRF binding (P = 0.0244);Gain of MoRF binding (P = 0.0244);
MVP
0.97
MPC
0.033
ClinPred
1.0
D
GERP RS
6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.98

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: chr2-47703547; API