2-47471051-A-G

Variant names:

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

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]

MSH2 links:

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
MSH2	NM_000251.3 link	c.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
MSH2	ENST00000233146.7 link	c.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:

AN:

152232

Hom.:

Cov.:

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:

AN:

250860

Hom.:

AF XY:

0.0000884

AC XY:

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.:

Cov.:

AF XY:

0.0000852

AC XY:

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:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

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.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000989

AC:

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 01, 2022

CeGaT Center for Human Genetics Tuebingen

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) -

Feb 03, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2018

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 29, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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. -

not specified

Uncertain:1Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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 â€šÃ„ÃºWith Uncertain significanceâ€šÃ„Ã¹ 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

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

T;.;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

0.065

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

0.57

N;.;.;.

PrimateAI

Uncertain

0.56

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over