2-47463052-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_000251.3(MSH2):​c.1408G>C​(p.Val470Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V470E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MSH2
NM_000251.3 missense

Scores

6
11
2

Clinical Significance

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

Conservation

PhyloP100: 6.37
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 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH2NM_000251.3 linkc.1408G>C p.Val470Leu missense_variant Exon 9 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.1408G>C p.Val470Leu missense_variant Exon 9 of 16 1 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

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

ClinVar

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

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Apr 04, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MSH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 470 of the MSH2 protein (p.Val470Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. -

Hereditary cancer-predisposing syndrome Uncertain:1
Feb 11, 2025
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting, BS3 c.1408G>C, located in exon 9 of the MSH2 gene, is predicted to result in the substitution of Val by Leu at codon 470, p.(Val470Leu).It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). Computational tools for this variant suggests no significant impact on splicing but the effect of the variant on protein function is indeterminate (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.18). A functional study based on cell viability assay in HEK293 or HAP1 cells using 6-TG treatment demonstrates normal function for this variant, with a LOF score -2,04 (PMID 33357406) (BS3).To our knowledge, relevant clinical data has not been reported for this variant. This variant has been reported in the ClinVar database (1x uncertain significance), but it has not been reported neither in InSiGHT nor in LOVD databases. Based on currently available information, the variant c.1408G>C should be considered an uncertain significance variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D;.;.;.
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.88
D;D;D;D
MetaSVM
Uncertain
0.75
D
MutationAssessor
Uncertain
2.5
M;.;.;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-1.7
N;N;.;N
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0060
D;D;.;D
Sift4G
Uncertain
0.011
D;D;.;D
Polyphen
0.88
P;.;.;P
Vest4
0.75
MutPred
0.79
Loss of methylation at K471 (P = 0.0391);.;Loss of methylation at K471 (P = 0.0391);Loss of methylation at K471 (P = 0.0391);
MVP
0.93
MPC
0.012
ClinPred
0.96
D
GERP RS
4.5
Varity_R
0.69
gMVP
0.58

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: rs1391167729; hg19: chr2-47690191; API