2-47471051-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBP6

The NM_000251.3(MSH2):​c.1748A>T​(p.Asn583Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000442 in 1,356,148 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. N583S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

5
11
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:2

Conservation

PhyloP100: 3.81
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 Uncertain_significance. Variant got 1 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.926
BP6
Variant 2-47471051-A-T is Benign according to our data. Variant chr2-47471051-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229675.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=11}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH2NM_000251.3 linkuse as main transcriptc.1748A>T p.Asn583Ile missense_variant 11/16 ENST00000233146.7 NP_000242.1 P43246-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.1748A>T p.Asn583Ile missense_variant 11/161 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250860
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135694
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.00000442
AC:
6
AN:
1356148
Hom.:
0
Cov.:
22
AF XY:
0.00000588
AC XY:
4
AN XY:
680680
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:
0.00000492
Gnomad4 OTH exome
AF:
0.0000176
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:12Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Lynch syndrome 1 Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingCounsylJun 05, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalJul 26, 2022The MSH2 c.1748A>T (p.Asn583Ile) missense change has a maximum subpopulation frequency of 0.0029% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, however a functional assay using a massively parallel screen in human cells indicated that this variant is neutral (PMID: 33357406). This variant has been reported in individuals with colorectal cancer (PMID: 11376800, 19526325). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Mar 16, 2023This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsNov 27, 2023- -
Hereditary cancer-predisposing syndrome Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 02, 2023The p.N583I variant (also known as c.1748A>T), located in coding exon 11 of the MSH2 gene, results from an A to T substitution at nucleotide position 1748. The asparagine at codon 583 is replaced by isoleucine, an amino acid with dissimilar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This alteration was identified in an individual diagnosed with colorectal cancer (Dharwadkar P et al. Clin Gastroenterol Hepatol, 2022 Feb;20:353-361.e3). This alteration was also detected in a cohort of unrelated Brazilian individuals diagnosed with breast cancer (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitterclinical testingMendelicsApr 08, 2024- -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Nov 17, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 21, 2023This missense variant replaces asparagine with isoleucine at codon 583 in the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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). This variant has been reported in individuals affected with colorectal cancer (PMID: 11376800, 19526325, 33359728). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases, 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/250860 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:2
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The MSH2 p.Asn583Ile variant was identified in 2 of 1876 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Berginc 2009, Potočnik 2001). The variant was also identified in dbSNP (ID: rs201118107) as "With Uncertain significance allele" and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Counsyl and Color). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 3 of 245916 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33576 chromosomes (freq: 0.00003) and European in 2 of 111446 chromosomes (freq: 0.00002); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asn583 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthApr 10, 2024This missense variant replaces asparagine with isoleucine at codon 583 in the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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). This variant has been reported in individuals affected with colorectal cancer (PMID: 11376800, 19526325, 33359728). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases, 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/250860 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:2
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesApr 01, 2020The MSH2 c.1748A>T; p.Asn583Ile variant (rs201118107) is reported in the literature in the germline of individuals with colorectal cancer (Berginc 2009, Potocnik 2001). This variant is also reported in the ClinVar database (Variation ID: 229675). It is only observed on 3 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 583 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Berginc G et al. Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome. Fam Cancer. 2009;8(4):421-9. Potocnik U et al. Causes of microsatellite instability in colorectal tumors: implications for hereditary non-polyposis colorectal cancer screening. Cancer Genet Cytogenet. 2001 Apr 15;126(2):85-96. -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoSep 16, 2020- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 16, 2020DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1748A>T, in exon 11 that results in an amino acid change, p.Asn583Ile. This sequence change has been described in the gnomAD database in three individuals (dbSNP rs201118107). The p.Asn583Ile change has been described in several individuals with colorectal cancer (PMIDs: 11376800, 19526325). The p.Asn583Ile change affects a moderately conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Asn583Ile substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Asn583Ile change remains unknown at this time. -
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 19, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.79
D;.;.;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.93
D;D;D;D
MetaSVM
Uncertain
0.63
D
MutationAssessor
Uncertain
2.7
M;.;.;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-5.0
D;D;.;D
REVEL
Pathogenic
0.79
Sift
Uncertain
0.028
D;D;.;D
Sift4G
Benign
0.10
T;T;.;T
Polyphen
0.47
P;.;.;P
Vest4
0.81
MutPred
0.84
Gain of ubiquitination at K579 (P = 0.1103);.;Gain of ubiquitination at K579 (P = 0.1103);Gain of ubiquitination at K579 (P = 0.1103);
MVP
0.93
MPC
0.020
ClinPred
0.95
D
GERP RS
5.9
Varity_R
0.90
gMVP
0.62

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: rs201118107; hg19: chr2-47698190; API