2-47416398-C-G

Variant names:

• chr2-47416398-C-G
• rs267607939
• NM_000251.3:c.1045C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PM1 PM5 PP3_Strong BP6

The NM_000251.3(MSH2):​c.1045C>G​(p.Pro349Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,108 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. P349R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:10
• Conservation: PhyloP100: 7.76
• Publications: 18 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_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 40 uncertain in NM_000251.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47416399-CT-GC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 561171.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• BP6: Variant 2-47416398-C-G is Benign according to our data. Variant chr2-47416398-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 90512.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1045C>G	p.Pro349Ala	missense_variant	Exon 6 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1045C>G	p.Pro349Ala	missense_variant	Exon 6 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.0000915 AC: 23 AN: 251434 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000459 AC: 67 AN: 1460988 Hom.: 0 Cov.: 30 AF XY: 0.0000509 AC XY: 37 AN XY: 726870

African (AFR) AF: 0.0000598 AC: 2 AN: 33458

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111208

Other (OTH) AF: 0.000116 AC: 7 AN: 60368

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.000328 AC: 5 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:3

Aug 09, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 16, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Jan 10, 2020

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 11, 2017

True Health Diagnostics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 24, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BS3, PP3_Moderate, BP5 c.1045C>G located in exon 6 of the MSH2 gene, is predicted to result in the substitution of proline by alanine at codon 349, p.(Pro349Ala). This variant is found in 77/1613108 alleles in the gnomAD v4.1.0 dataset, with a filtering allele frequency of 0.023% (Admixed Americans subset) (BS1). Computational tools predict a deleterious effect of the variant on protein function (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.865; PP3_Moderate). A functional study based on cell viability assay in HEK293 or HAP1 cells using 6-TG treatment demonstrates normal function for this variant, with a LOF score of -2.19 (PMID: 33357406) (BS3). Similar results were obtained in a methylation-tolerance functional assay (PMID: 30998989). It has been reported in at least two CRC tumors with no loss of MMR protein expression (internal data, Bouvet_2019) (BP5). There is another missense variant (c.1046C>G (p.Pro349Arg)) classified by Insight as pathogenic in the same codon. The variant was also identified in the ClinVar database (9x uncertain significance, 6x likely benign, 3x benign) and in the LOVD database (3x uncertain significance, 2x not classified) and classified as uncertain significance variant (�Insufficient evidence�) in InSiGHT database. Based on currently available information, the variant c.1045C>G is classified as a benign variant according to the ClinGen-CRC_ACMG_Specifications_MSH2_v1.0.0.

Lynch syndrome 1 Uncertain:2 Benign:1

Dec 09, 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. 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].

May 28, 2019

Mendelics

Significance: Uncertain significance

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

not specified Uncertain:1 Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2025

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.1045C>G (p.Pro349Ala) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4.8e-05 in 1613108 control chromosomes, predominantly at a frequency of 0.00091 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057). c.1045C>G has been observed in individuals affected with colorectal cancer / (suspected) Lynch syndrome (Hansen_2017, Akcay_2020, Ferrer-Avargues_2021) and with other tumor phenotypes, which were mostly outside of the Lynch syndrome tumor spectrum (e.g. Rubio-Del-Campo_2008, Cragun_2014, Landa_2016, Jalkh_2017, Zidan_2017, Dorling_2021), but the variant was also found in healthy controls (e.g. Dorling_2021). In addition, in one of the reported CRC cases a co-occurrence with other pathogenic variant has been reported (MSH2 c.223_224del (p.Leu75AlafsTer), Ferrer-Avargues_2021), providing supporting evidence for a benign role. Multiple publications reported experimental evidence evaluating an impact on protein function, and all of them showed no damaging effect for this variant (Houlleberghs_2016, Bouvet_2019, Jia_2021). Of note, several other missense variants affecting the same residue (e.g. P349L and P349R) were found to be deleterious in these assays (Houlleberghs_2016, Jia_2021), suggesting that although P349 may be critical for protein function, the effect of missense variants at this residue strongly depends on the specific amino acid substitution. ClinVar contains an entry for this variant (Variation ID: 90512). Based on the evidence outlined above, the variant was classified as likely benign.

May 13, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro349Ala variant in MSH2 is classified as likely benign because it has been identified in 0.08% (8/10366) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1.

not provided Uncertain:1 Benign:1

Sep 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 30998989, 29887214, 18325052, 31297992, 30306255, 28873162, 17720936, 17531815, 21239990, 18951462, 15342696, 28640387, 28828701, 26951660, 28301460, 28584132, 26878173, 27720647, 28195393, 28202063, 24506336, 22949387, 26333163, 25203624, 25637381, 24763289)

Dec 22, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.1045C>G (p.Pro349Ala) variant has been reported in the published literature in individuals affected with colorectal cancer (PMIDs: 28195393 (2017), 28640387 (2017), 32658311 (2021), 33630411 (2021)), breast cancer (PMIDs: 28202063 (2017), 30306255 (2018), 34371384 (2021), 35245693 (2022), 35264596 (2022), 35534704 (2022)), and cervical cancer (PMID: 24506336 (2014)). This variant was also reported to occur with a pathogenic variant in the same MSH2 gene (PMID: 33630411 (2021)) or the BRCA1 gene (PMID: 28202063 (2017)), suggesting this variant may not be the primary cause of disease. Functional studies predicted the variant to be neutral using indirect cell survival assays of MMR function (PMIDs: 26951660 (2016), 30998989 (2019), 33357406 (2021)), however, different amino acid changes at the same codon, p.Pro349Leu and p.Pro349Arg, showed defective MMR function and further research is needed. The frequency of this variant in the general population, 0.00077 (8/10366 chromosomes in Ashkenazi Jewish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Hereditary nonpolyposis colon cancer Uncertain:1

Jan 05, 2021

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (ID:90512) which has conflicting classifications. Based on data in gnomAD, the frequency in the Latino population and Ashkenazi Jewish population is higher than expected for a pathogenic MSH2 variant. In a Lebanese family, the variant has been observed to co-occur with a pathogenic variant that could explain the patient disease phenotype (PMID 28202063).

Papillary renal cell carcinoma type 1 Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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

Lynch syndrome Benign:1

Apr 29, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Benign:1

Sep 10, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ClinGen InSiGHT ACMG MSH2 v1.0.0 criteria we chose these criteria: PP3 (medium pathogenic): prior Propability: 0,87: mod, BS1 (strong benign): GnomAD v4 Grpmax filtering allele frequency = 0.0002341 (thus, ≥ 0.0001 and < 0.001 (0.01-0.1%)), BS3 (strong benign): PMID: 33357406 / Jia et. al (2021): LOF Score of -2.77 in functional assay.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;.;.;.
PhyloP100		7.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.9	D;D;.;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Vest4		0.95
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.70
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267607939; hg19: chr2-47643537;