rs587781447

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PM2PP3_ModerateBP6

The NM_000251.3(MSH2):​c.260C>A​(p.Ser87Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,611,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S87C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

6
12
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 5.11
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 was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 17 uncertain in NM_000251.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.849
BP6
Variant 2-47408449-C-A is Benign according to our data. Variant chr2-47408449-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 231690.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH2NM_000251.3 linkc.260C>A p.Ser87Tyr missense_variant Exon 2 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.260C>A p.Ser87Tyr missense_variant Exon 2 of 16 1 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
AF:
0.00000661
AC:
1
AN:
151214
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000661
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000797
AC:
2
AN:
250910
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460314
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
726470
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33426
American (AMR)
AF:
0.00
AC:
0
AN:
44674
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26106
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39658
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86084
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53358
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5746
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1110942
Other (OTH)
AF:
0.00
AC:
0
AN:
60320
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000661
AC:
1
AN:
151214
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
73748
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41058
American (AMR)
AF:
0.0000661
AC:
1
AN:
15132
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5170
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4796
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10368
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67930
Other (OTH)
AF:
0.00
AC:
0
AN:
2070
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Nov 03, 2022
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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. -

Jul 24, 2024
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces serine with tyrosine at codon 87 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/250910 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 1 Uncertain:1
Mar 24, 2022
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The MSH2 c.260C>A (p.Ser87Tyr) missense change has a maximum subpopulation frequency 0.0054% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/2-47635588-C-A). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in individuals with breast cancer (PMID: 32547938) and one individual with relapsed pediatric T-lymphoblastic leukemia (PMID: 32547938). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, PP3. -

Lynch syndrome Uncertain:1
Aug 13, 2024
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces serine with tyrosine at codon 87 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/250910 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
May 16, 2018
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is denoted MSH2 c.260C>A at the cDNA level, p.Ser87Tyr (S87Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCT>TAT). This variant was not observed in a cohort of individuals diagnosed with colon cancer, however it was identified in an unaffected control (Arora 2015). MSH2 Ser87Tyr was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Tyrosine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Ser87Tyr occurs at a position that is conserved in mammals and is located in the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Ser87Tyr is a pathogenic variant or a benign variant. We consider it to be a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Aug 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.75
D;D;.;.;.
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.92
D;D;D;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.85
D;D;D;D;D
MetaSVM
Pathogenic
0.81
D
MutationAssessor
Uncertain
2.9
M;.;.;.;.
PhyloP100
5.1
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-3.7
D;D;D;.;D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0020
D;D;D;.;D
Sift4G
Uncertain
0.0060
D;D;D;.;D
Polyphen
0.99
D;.;.;.;D
Vest4
0.70
MutPred
0.57
Loss of MoRF binding (P = 0.1298);.;.;Loss of MoRF binding (P = 0.1298);Loss of MoRF binding (P = 0.1298);
MVP
0.88
MPC
0.028
ClinPred
0.97
D
GERP RS
5.3
Varity_R
0.92
gMVP
0.58
Mutation Taster
=36/64
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs587781447; hg19: chr2-47635588; API