chr2-47471062-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3PP5_Moderate

The NM_000251.3(MSH2):​c.1759G>T​(p.Gly587Cys) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G587R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MSH2
NM_000251.3 missense, splice_region

Scores

12
6
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.22
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.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-47471062-G-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.823
PP5
Variant 2-47471062-G-T is Pathogenic according to our data. Variant chr2-47471062-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 428463.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47471062-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH2NM_000251.3 linkc.1759G>T p.Gly587Cys missense_variant, splice_region_variant Exon 11 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.1759G>T p.Gly587Cys missense_variant, splice_region_variant Exon 11 of 16 1 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
20
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1
Apr 22, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1759G>T pathogenic mutation (also known as p.G587C), located in coding exon 11 of the MSH2 gene, results from a G to T substitution at nucleotide position 1759. The amino acid change results in glycine to cysteine at codon 587, an amino acid with highly dissimilar properties. However, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH2 expression by immunohistochemistry (Ambry internal data).This mutation was reported in a proband with HNPCC, and RNA analysis confirmed it resulted in aberrant splicing yielding p.Ser554Argfs*11 (Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31). In addition, an ex vivo minigene splicing assay on genomic DNA revealed exon 11 skipping as a result of another alteration at this position (c.1759G>C; p.G587R), which as been detected in one suspected Lynch syndrome family and has been classified as pathogenic by multifactorial analysis (Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Tournier I et al. Hum. Mutat. 2008 Dec;29:1412-24; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-115). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.;.;.
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.82
D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Pathogenic
3.0
M;.;.;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-7.4
D;D;.;D
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0020
D;D;.;D
Sift4G
Uncertain
0.0050
D;D;.;D
Polyphen
1.0
D;.;.;D
Vest4
0.83
MutPred
0.49
Loss of glycosylation at S586 (P = 0.0485);.;Loss of glycosylation at S586 (P = 0.0485);Loss of glycosylation at S586 (P = 0.0485);
MVP
0.97
MPC
0.035
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.98
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.97
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.97
Position offset: 0

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: rs63751140; hg19: chr2-47698201; API