rs33946261

Variant names:

• chr2-47403329-C-G
• rs33946261
• NM_000251.3:c.138C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-47403329-C-G
• chr2-47403329-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PP3_Moderate BP6_Very_Strong

The NM_000251.3(MSH2):​c.138C>G​(p.His46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000441 in 1,606,276 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 Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:5 B:17 O:1
• Conservation: PhyloP100: 2.26

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• BP6: Variant 2-47403329-C-G is Benign according to our data. Variant chr2-47403329-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 90654.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47403329-C-G is described in Lovd as [Likely_benign]. Variant chr2-47403329-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.138C>G	p.His46Gln	missense_variant	Exon 1 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.138C>G	p.His46Gln	missense_variant	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000218 AC: 50 AN: 229550 Hom.: 1 AF XY: 0.000271 AC XY: 34 AN XY: 125496

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000613

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: 0.000467

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000465 AC: 676 AN: 1454024 Hom.: 0 Cov.: 31 AF XY: 0.000443 AC XY: 320 AN XY: 722674

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000115

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.000576

Gnomad4 OTH exome AF: 0.000483

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74380

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000240 AC: 29

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5 Benign:17 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:3 Other:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 5 labs classify as VUS, including expert panel. No new information suggesting disease-causing role since expert classification. -

Jul 10, 2023

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.138C>G (p.His46Gln) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 247506 control chromosomes, predominantly at a frequency of 0.00047 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00026 vs 0.00057), allowing no conclusion about variant significance. c.138C>G has been identified in numerous patients with colorectal cancer (CRC), prostate cancer and ovarian cancer without strong evidence for causality (Examples: Barnetson_2008, Hampel_2005, Pal_2012, Grant_2015, Arora_2015, Lagerstedt-Robinson_2016, Maxwell_2016, Ghazani_2017, Raskin_2017, Rossi_2017, Velho_2018, Young_2018, Li_2020, Li_2021). In several studies, microsatellite stability in tumor tissues was assayed and found to be stable and immunohistochemical studies showed the presence of MSH2 (and MSH6) protein (Barnetson_2008, Hampel_2005, Arora_2015). In one patient, MLH1 was found to be hypermethylated at its promoter. This decreases the likelihood of this variant being a cause of germline inherited cancer as MLH1 promoter hypermethylation is associated with sporadic cancers instead of inherited cancers (Hampel_2005). In addition, one study reported the variant to not segregate with disease in a family, i.e. three affected individuals did not carry the variant, while three unaffected individuals carried the variant (Hansen_2017). Two independent in vitro functional studies demonstrated that the variant of interest does not impact mismatch repair activity (Houlleberghs_2016, Jia_2021). Another study that was performed on lymphoblastoid cells from a sporadic CRC patient who carried the variant, found increased level of DNA damage after UV treatment (Arora_2015). Since the patient's tumor sample showed stable microsatellites and normal expression of mismatch repair (MMR) proteins, the authors postulated that beyond its function in MMR, this variant might predispose to DNA double-strand breaks by affecting homologous recombinational repair. The following publications have been ascertained in the context of this evaluation (PMID: 18383312, 18033691, 15872200, 15520370, 23047549, 16574953, 25479140, 26951660, 27601186, 27153395, 28195393, 26344056, 28874130, 29212164, 28125075, 29945567, 29368341, 30374176, 31391288, 33471991, 33357406, 34117267). Multiple submitters including one expert panel (InSiGHT), have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=12) and VUS (n=3). 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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Apr 19, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Uncertain:1 Benign:3

Feb 27, 2023

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Apr 22, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.138C>G variant is classified as Likely Benign (BS4, BP6, PP3) The MSH2 c.138C>G variant is a single nucleotide change in exon 1 of 16 of the MSH2 gene, which is predicted to change the amino acid histidine at position 46 in the protein to glutamine. This variant does not segregate with disease (BS4). PMID: 28195393- segregation analysis does not support pathogenicity. Variant identified in 0 out of 3 affected family members and 3 out of 9 unaffected family members. PMID:30374176 - family studies do not support pathogenicity -

Dec 03, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. -

Lynch syndrome Benign:3

Dec 19, 2018

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

Multifactorial likelihood analysis posterior probability <0.05 -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The MSH2 variant designated as NM_000251.2:c.138C>G (p.His46Gln) is classified as likely benign. This variant is listed in population databases and is found in approximately 1 out of 950 individuals of European ancestry, which is not consistent with the prevalence of Lynch syndrome. The variant has been seen in tumors with molecular phenotypes inconsistent with Lynch syndrome (InSiGHT.org). Based on in-silico scores the variant has a prior probability of pathogenicity of 10% or lower (Thompson et al., 2013, PMID:22949379). Cosegregation analysis of two observed families was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) yielded a combined likelihood ratio of 1.52:1 for this variant explaining cancer in the families (Thompson, et al., 2003, PMID:2900794). However, Bayesian analysis integrating all data (Tavtigian et al, 2018, PMID:29300386) gave a less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH2 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Hereditary cancer-predisposing syndrome Benign:3

Dec 13, 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. -

Jun 26, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 03, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Apr 14, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15872200, 27153395, 18383312, 24728327, 25637381, 23047549, 19389263, 15520370, 16741161, 18033691, 27601186, 28195393, 26333163, 26344056, 29212164, 28330790, 28125075, 28874130, 24055113, 25479140, 26951660, 29368341, 30374176, 31297992) -

Nov 02, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Uncertain:1

Dec 09, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

MSH2-related disorder Benign:1

Aug 14, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 p.His46Gln variant was identified in 8 of 8869 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch Syndrome, colorectal cancer, multiple adenomas, pancreatic cancer, or ovarian cancer and was identified in 1 of 3326 control chromosomes (frequency: 0.0003) from healthy individuals (Barnetson 2008, Fearnhead 2004, Grant 2015, Hampel 2005, Hansen 2017, Lagerstedt-Robinson 2016, Pal 2012, Rossi 2017). Segregation analysis of the variant in one family with colorectal cancer did not support pathogenicity as the variant was seen in both affected and unaffected family members (Hansen 2017). One study found the variant to be non-pathogenic using a site-specific mutagenesis screen (Houlleberghs 2016). The variant was identified in dbSNP (ID: rs33946261) as “With Likely benign, other allele”, ClinVar (classified as uncertain significance by an InSiGHT expert panel in 2015, Invitae, Color, and four other submitters; and as likely benign by GeneDx, Ambry Genetics, and one other submitter), UMD-LSDB (classified as UV), and Mismatch Repair Genes Variant Database. The variant was identified in control databases in 58 of 256068 chromosomes (1 homozygous) at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 55 (1 homozygous) of 115892 chromosomes (freq: 0.0005), African in 1 of 21856 chromosomes (freq: 0.00005), and Latino in 2 of 32620 chromosomes (freq: 0.00006); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.His46 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Benign:1

Apr 25, 2022

Fulgent Genetics, Fulgent Genetics

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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.6	H;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.7	D;.;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		0.99	D;.;D
Vest4		0.96
MutPred		0.93		Loss of catalytic residue at E48 (P = 0.1192);Loss of catalytic residue at E48 (P = 0.1192);Loss of catalytic residue at E48 (P = 0.1192);
MVP		0.98
MPC		0.032
ClinPred		0.79	D
GERP RS		4.6
Varity_R		0.98
gMVP		0.80

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

Other links and lift over

dbSNP: rs33946261; hg19: chr2-47630468;