rs63750070

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000251.3(MSH2):​c.518T>A​(p.Leu173Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L173R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

MSH2
NM_000251.3 missense

Scores

13
4
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.96
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 Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 14 uncertain in NM_000251.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-47410245-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 91122.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MSH2NM_000251.3 linkuse as main transcriptc.518T>A p.Leu173Gln missense_variant 3/16 ENST00000233146.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.518T>A p.Leu173Gln missense_variant 3/161 NM_000251.3 P1P43246-1

Frequencies

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
D;D;.;.;.
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Pathogenic
0.81
D
MutationAssessor
Pathogenic
3.2
M;.;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.48
T
PROVEAN
Pathogenic
-4.7
D;D;D;.;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0010
D;D;D;.;D
Sift4G
Uncertain
0.0030
D;D;D;.;D
Polyphen
0.99
D;.;.;.;D
Vest4
0.91
MutPred
0.90
Gain of methylation at K172 (P = 0.0539);.;.;Gain of methylation at K172 (P = 0.0539);Gain of methylation at K172 (P = 0.0539);
MVP
0.98
MPC
0.033
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.98
gMVP
0.87

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: chr2-47637384; API