2-47471051-A-G

Variant names:

• chr2-47471051-A-G
• rs201118107
• NM_000251.3:c.1748A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS3

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:10
• Conservation: PhyloP100: 3.81
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.1748A>G	p.Asn583Ser	missense	Exon 11 of 16	NP_000242.1
	MSH2	NM_001406674.1		c.1748A>G	p.Asn583Ser	missense	Exon 11 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.1748A>G	p.Asn583Ser	missense	Exon 11 of 18	NP_001393560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1748A>G	p.Asn583Ser	missense	Exon 11 of 16	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.1748A>G	p.Asn583Ser	missense	Exon 11 of 16	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.1748A>G	p.Asn583Ser	missense	Exon 11 of 17	ENSP00000495455.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152232 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000997 AC: 25 AN: 250860 AF XY: 0.0000884

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 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

African (AFR) AF: 0.0000954 AC: 3 AN: 31442

American (AMR) AF: 0.000157 AC: 7 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25388

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39084

South Asian (SAS) AF: 0.0000476 AC: 4 AN: 83948

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5410

European-Non Finnish (NFE) AF: 0.0000955 AC: 97 AN: 1016214

Other (OTH) AF: 0.0000528 AC: 3 AN: 56786

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74384

African (AFR) AF: 0.000145 AC: 6 AN: 41472

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000138 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:8 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign: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:1 Benign:3

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.

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 29, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

not specified Uncertain:1 Benign: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

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

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

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 v4.9

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
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.57	N
PhyloP100		3.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.30
Sift	Benign	0.44	T
Sift4G	Benign	0.83	T
Polyphen		0.0050	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
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs201118107; hg19: chr2-47698190;