2-47463128-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The ENST00000233146.7(MSH2):​c.1484C>T​(p.Thr495Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T495A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

MSH2
ENST00000233146.7 missense

Scores

6
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 2.75
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 Likely_benign. Variant got -1 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 14 uncertain in ENST00000233146.7
BP4
Computational evidence support a benign effect (MetaRNN=0.1774514).
BP6
Variant 2-47463128-C-T is Benign according to our data. Variant chr2-47463128-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185360.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH2NM_000251.3 linkuse as main transcriptc.1484C>T p.Thr495Ile missense_variant 9/16 ENST00000233146.7 NP_000242.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.1484C>T p.Thr495Ile missense_variant 9/161 NM_000251.3 ENSP00000233146 P1P43246-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152130
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251298
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135832
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461672
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727142
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:
0.00000719
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152130
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 27, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 26, 2023This missense variant replaces threonine with isoleucine at codon 495 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in a Lynch syndrome family, however, a pathogenic variant in MSH6 was also identified that could explain the observed phenotype (PMID: 27601186). This variant has been identified in 2/251298 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJun 26, 2023This missense variant replaces threonine with isoleucine at codon 495 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in a Lynch syndrome family, however, a pathogenic variant in MSH6 was also identified that could explain the observed phenotype (PMID: 27601186). This variant has been identified in 2/251298 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 30, 2015This variant is denoted MSH2 c.1484C>T at the cDNA level, p.Thr495Ile (T495I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Thr495Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Thr495Ile occurs at a position that is not conserved and is located within the clamp domain (Lutzen 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH2 Thr495Ile is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 29, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.040
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.40
T;.;.;.
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.0081
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Uncertain
0.87
D;D;D;D
M_CAP
Benign
0.032
D
MetaRNN
Benign
0.18
T;T;T;T
MetaSVM
Benign
-0.66
T
MutationAssessor
Benign
-0.69
N;.;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.84
N;N;.;N
REVEL
Uncertain
0.46
Sift
Benign
0.18
T;T;.;T
Sift4G
Benign
0.16
T;T;.;T
Polyphen
0.0010
B;.;.;B
Vest4
0.81
MutPred
0.52
Loss of disorder (P = 0.0568);.;Loss of disorder (P = 0.0568);Loss of disorder (P = 0.0568);
MVP
0.94
MPC
0.0064
ClinPred
0.38
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.23
gMVP
0.21

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: rs756516114; hg19: chr2-47690267; API