rs63751455

Variant names:

• chr2-47412496-G-A
• rs63751455
• NM_000251.3:c.728G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47412496-G-A
• chr2-47412496-G-C
• chr2-47412496-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_000251.3(MSH2):​c.728G>A​(p.Arg243Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,611,374 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. R243W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:4
• Conservation: PhyloP100: 9.62
• Publications: 16 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824
• BP6: Variant 2-47412496-G-A is Benign according to our data. Variant chr2-47412496-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 91189.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.728G>A	p.Arg243Gln	missense_variant	Exon 4 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.728G>A	p.Arg243Gln	missense_variant	Exon 4 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251398 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1459344 Hom.: 0 Cov.: 29 AF XY: 0.0000207 AC XY: 15 AN XY: 726218

African (AFR) AF: 0.0000299 AC: 1 AN: 33412

American (AMR) AF: 0.0000895 AC: 4 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1109928

Other (OTH) AF: 0.0000995 AC: 6 AN: 60290

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Sep 01, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 13, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.728G>A (p.Arg243Gln) variant has been reported in the published literature in individuals with colorectal cancer (PMID: 21311894 (2011)), Lynch syndrome (PMIDs: 27468915 (2017) and 16395668 (2006)), and constitutional mismatch repair deficiency syndrome (PMIDs: 26116798 (2015) and 16395668 (2006)). It has also been seen in breast cancer cases as well as in unaffected individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). Functional studies demonstrated that the effect on protein function were inconclusive (PMIDs: 36011265 (2022), 33357406 (2021), 30998989 (2019), 26247049 (2015), and 16395668 (2006)). The frequency of this variant in the general population, 0.000016 (4/251398 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Nov 22, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with a personal or family history including colorectal and other cancers (Auclair 2006, Moussa 2011, Ziada-Bouchaar 2016, Mandelker 2017); Published functional studies demonstrate lack of cell survival following MNNG-induced DNA damage, suggesting neutrality (Bouvet 2019); This variant is associated with the following publications: (PMID: 16395668, 21311894, 18383312, 26247049, 27468915, 26333163, 28873162, 26116798, 24953332, 31248416, 30998989) -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:2

Aug 08, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.728G>A (p.Arg243Gln) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251398 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.728G>A has been reported in the literature in individuals affected with hereditary nonpolyposis colorectal cancer and colorectal cancer (Auclair_2006, Zaida-Bouchaar_2017, Castillejo_2014, Moussa_2011, Bodo_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variants were reported in 4 patients described in the literature, including the co-occurrence of homozygous PMS2 large deletions in a patient with CMMR (MSH2 c.1413dupA, p.Pro472ThrfsX4; MSH2 c.1030C>T, p.Gln344X ; PMS2 c.2275+210_2446-1356del, p.Ala759Glyfs*8), providing supporting evidence for a benign role. Two publications report splicing evidence showing no impact on splicing by the variant (Van der Klift_2015, Auclair_2006). Additionally, another functional study based on the proportion of cells that undergo death following exposure to methylating agents reported the variant to be neutral (Bouvet_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant. -

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 1 Uncertain:1 Benign:1

Dec 05, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely 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]. -

Dec 22, 2015

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Hereditary cancer-predisposing syndrome Benign:2

Mar 30, 2021

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. -

Feb 23, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Uncertain:1

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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.Arg243Gln variant was identified in 3 of 224 proband chromosomes (frequency: 0.01) from Algerian, French and Tunisian individuals or families with Lynch syndrome or CRC (Ziada-Bouchaar 2017, Moussa 2011, Auclair 2006). In these studies, 2 of the probands had co-occurring pathogenic MSH2 variants (c.1030C>T/ p.Gln344X and c.1413dupA/p.Pro472ThrfsX4). The variant was also identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 variant (c.7234_7235insG, p.Thr2412Serfs*2) increasing the likelihood the MSH2 c.728G>A variant may not have clinical significance. In functional studies using patient RNA analysis and minigene splicing, both assays showed normal splicing (van der Klift 2015, Auclair 2006). A bioinformatics tool, multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR), classified the variant as neutral (Chao 2008). The variant was also identified in dbSNP (ID: rs63751455) “With Uncertain significance allele”, ClinVar (classified uncertain significance, reviewed by an expert panel (2013); submitters: INSIGHT, Invitae, Ambry Genetics, GeneDx and 3 other laboratories), and UMD-LSDB (4x classified as UV). The variant was identified in control databases in 3 of 246198 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: Latino in 2 of 33578 chromosomes (freq: 0.00006) and European Non-Finnish in 1 of 111672 chromosomes (freq: 0.000009); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, European Finnish and South Asian populations. The p.Arg243 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Gln variant may impact the protein; however, this information is not predictive enough to assume 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. This variant is classified as a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	2.9	M;.;.;.
PhyloP100		9.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D;D;.;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0060	D;D;.;D
Sift4G	Uncertain	0.016	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.82
MutPred		0.40		Loss of MoRF binding (P = 0.0218);.;Loss of MoRF binding (P = 0.0218);Loss of MoRF binding (P = 0.0218);
MVP		0.95
MPC		0.033
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.85
gMVP		0.58
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs63751455; hg19: chr2-47639635;