2-47471051-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS3BP4

This summary comes from the ClinGen Evidence Repository: The MSH2 c.1748A>G variant is predicted as a missense variant, p.(Asn583Ser). It has been identified at an MCAF 95% of 0.00934% in gnomAD all non-cancer v2.1.1 and Grpmax AF of 0.007999% in gnomAD v4.1. It is not predicted to affect protein function (Prior_utah (MAPP/PP2 < than 0.11; BP4). The variant did not affect the splicing (pCAS minigene [Pascaline Gaildrat & Stephanie Baert-Desurmont]) and showed proficient function in a calibrated functional assay (PMID 33357406; BS3). The variant was found in a patient with CRC showing MSS/IHC normal (FHCRC CCFR, Insight database). According to the current guidelines, the variant is classified as likely benign. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA019161/MONDO:0005835/137

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

5
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:10

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 Likely_benign. Variant got -5 ACMG points.

BP4
For more information check the summary or visit ClinGen Evidence Repository.
BS3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH2NM_000251.3 linkc.1748A>G p.Asn583Ser missense_variant Exon 11 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.1748A>G p.Asn583Ser missense_variant Exon 11 of 16 1 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152232
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000997
AC:
25
AN:
250860
Hom.:
0
AF XY:
0.0000884
AC XY:
12
AN XY:
135694
show subpopulations
Gnomad AFR exome
AF:
0.000124
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000132
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000870
AC:
118
AN:
1356144
Hom.:
0
Cov.:
22
AF XY:
0.0000852
AC XY:
58
AN XY:
680678
show subpopulations
Gnomad4 AFR exome
AF:
0.0000954
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000256
Gnomad4 SAS exome
AF:
0.0000476
Gnomad4 FIN exome
AF:
0.0000563
Gnomad4 NFE exome
AF:
0.0000955
Gnomad4 OTH exome
AF:
0.0000528
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152232
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.000145
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000198
Hom.:
0
Bravo
AF:
0.000181
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000989
AC:
12
EpiCase
AF:
0.000164
EpiControl
AF:
0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:10
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:3
Jan 10, 2018
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 15, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25637381, 23047549, 22703879, 12658575, 18383312, 26898890, 27153395, 27600092, 26333163, 27720647, 30998989, 31159747) -

Jul 13, 2012
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Aug 01, 2018
GeneKor MSA
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 07, 2024
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 01, 2018
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 29, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

not specified Uncertain:1Benign:1
Sep 26, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MSH2 c.1748A>G (p.Asn583Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250860 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.0001 vs 0.00057), allowing no conclusion about variant significance.c.1748A>G has been reported in the literature in multiple individuals suspected of hereditary cancer (e.g. Tsaousis_2019, Li_2020, Maxwell_2016), however these reports do not provide unequivocal evidence for association of the variant with disease. The variant was found co-occuring with pathogenic MLH1 variants (c.589-1G>T; c.1852_1854delAAG [p.Lys618del]), providing supporting evidence for a benign role. In addition, a recent case-control study showed that this variant is not associated with breast cancer. Two publications found that the variant was functionally neutral in a cell survival assay (Bouvet_2019, Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 30998989, 26898890, 33471991, 33357406, 31391288, 27153395, 23047549, 31159747, 12658575). ClinVar contains an entry for this variant (Variation ID: 41645). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome Uncertain:1
Jun 05, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Colorectal cancer, non-polyposis Uncertain:1
Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Malignant tumor of breast Uncertain:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The MSH2 p.Asn583Ser variant was identified in 3 of 1836 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer, colon cancer, and atherosclerosis (Caminsky 2016, Johnston 2012, Wagner 2003). The variant was also identified in dbSNP (ID: rs201118107) as “With Uncertain significance” allele, ClinVar (classified as uncertain significance by GeneDx and 5 clinical laboratories; classified as likely benign by Ambry Genetics, Invitae), Clinvitae (classified as uncertain significance by ClinVar; classified as likely benign by Invitae), UMD-LSDB (3x as unclassified variant), and the Insight Hereditary Tumors Database. In UMD the variant was identified with a co-occurring pathogenic MLH1 variant c.1852_1854delAAG (p.Lys618del), increasing the likelihood that the p.Asn583Ser variant does not have clinical significance. In addition, a study by Wagner 2003 found this variant co-occurring with the MLH1 likely pathogenic variant c.589-1G>T. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 28 of 276902 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 4 of 24012 chromosomes (freq: 0.0002), Other in 2 of 6460 chromosomes (freq: 0.0003), Latino in 4 of 34414 chromosomes (freq: 0.0001), European in 15 of 126460 chromosomes (freq: 0.0001), East Asian in 1 of 18862 chromosomes (freq: 0.0001), Finnish in 1 of 25788 chromosomes (freq: 0.00004), and South Asian in 1 of 30760 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish population. The p.Asn583 residue is conserved in mammals but not in more distantly related organisms. However four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. This information is not predictive enough to assume 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. -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1
Jun 29, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:1
Dec 10, 2024
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Feb 03, 2025
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
Benign
0.067
BayesDel_addAF
Benign
-0.087
T
BayesDel_noAF
Benign
-0.13
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.38
T;.;.;.
Eigen
Benign
-0.18
Eigen_PC
Benign
0.065
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.93
D;D;D;D
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Benign
-0.35
T
MutationAssessor
Benign
0.57
N;.;.;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.0
N;N;.;N
REVEL
Uncertain
0.30
Sift
Benign
0.44
T;T;.;T
Sift4G
Benign
0.83
T;T;.;T
Polyphen
0.0050
B;.;.;B
Vest4
0.55
MVP
0.79
MPC
0.0071
ClinPred
0.021
T
GERP RS
5.9
Varity_R
0.26
gMVP
0.36

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.31
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.31
Position offset: -5

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; COSMIC: COSV104575462; API