NM_000251.3:c.2732T>G

Variant names:

• chr2-47482876-T-G
• rs41295182
• NM_000251.3:c.2732T>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000251.3(MSH2):​c.2732T>G​(p.Leu911Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,612,946 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).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:5
• Conservation: PhyloP100: 6.94

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 Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2732T>G	p.Leu911Arg	missense_variant	Exon 16 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2732T>G	p.Leu911Arg	missense_variant	Exon 16 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000680 AC: 17 AN: 249982 Hom.: 0 AF XY: 0.0000814 AC XY: 11 AN XY: 135098

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000141

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000118 AC: 172 AN: 1460754 Hom.: 0 Cov.: 31 AF XY: 0.000120 AC XY: 87 AN XY: 726562

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74348

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000989 AC: 12

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Jan 29, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate no damaging effect: variant did not result in 6TG-resistant colony formation, suggesting it does not affect mismatch repair function (Houlleberghs 2016); Observed in individuals with colon or epithelial ovarian cancer (Loader 2002, Barnetson 2008, Pal 2012, Ghazani 2017, Raskin 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29684080, 22949387, 16379545, 18033691, 23047549, 12537652, 26092435, 26333163, 19389263, 21153778, 28125075, 26951660, 29212164, 29641532, 32634176) -

Apr 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.2732T>G; p.Leu911Arg variant (rs41295182) is reported in the literature in individuals with colorectal cancer or ovarian cancer (Barnetson 2008, Pal 2012, Raskin 2017). However, this variant has also been identified in an apparently healthy individual (Karageorgos 2015), and one study classified this variant as benign based on lack of co-segregation with disease (Barnetson 2008). This variant is classified as both likely benign and uncertain significance in the ClinVar database (Variation ID: 91039). It is found in the general population with an overall allele frequency of 0.007% (19/281374 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.913). Based on available information, the clinical significance of this variant is uncertain at this time. References: Barnetson RA et al. Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer. Hum Mutat. 2008;29(3):367-374. PMID: 18033691. Karageorgos I et al. Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach. Hum Genomics. 2015;9(1):12. PMID: 26092435. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012;107(10):1783-1790. PMID: 23047549. Raskin L et al. Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort. Oncotarget. 2017;8(55):93450-93463. PMID: 29212164. -

Jun 07, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.2732T>G (p.Leu911Arg) variant has been reported in the published literature in individuals with endometrial cancer (PMID: 32634176 (2020)), colon cancer (PMID: 29212164 (2017), 28125075 (2017), 12537652 (2002)), and ovarian cancer (PMID: 23047549 (2012)). Although one study observed high microsatellite instability in a tumor and described this variant as deleterious, another study described this variant as benign because of a lack of co-segregation with disease (PMID: 12537652 (2002) and 18033691 (2008)). A mouse embryonic stem cell based functional study reported that this variant does not have a deleterious effect on MMR activity (PMID: 26951660 (2016), 33357406 (2021)). The frequency of this variant in the general population, 0.00013 (17/128602 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Uncertain:2 Benign:1

Aug 14, 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.2732T>G (p.Leu911Arg) results in a non-conservative amino acid change located in the Helix-turn-helix domain (aa 856-934) (Houlleberghs_2016) 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 6.8e-05 in 251846 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (6.8e-05 vs 0.00057), allowing no conclusion about variant significance. c.2732T>G has been reported in the literature in individuals affected with colon cancer (e.g. Loader_2002, Barnetson_2008, Ghazani_2017, Raskin_2017), in a patient with ovarian cancer (Pal_2012), and in a patient with endometrial and breast cancer (Singh_2020). The variant was also found in unaffected individuals (Karageorgos_2015, Arora_2015). One of these studies reported the variant not to segregate with the disease in a family (Barnetson_2008). At least one publication reported experimental evidence evaluating an impact on protein function, and showed no damaging effect for this variant on MMR activity in mouse embryonic stem cells (Houlleberghs_2016). An additional sstudy reported the vairant to be neutral using a combination of deep mutational scanning with established MMR assay (Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 18033691, 23047549, 26092435, 26951660, 26344056, 29212164, 28125075, 12537652, 32634176, 33357406). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments ranging from VUS to likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

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: Multiple reports describe as VUS/benign, ExAC: 0.02% (12/64562) European chromosomes -

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:2 Benign:1

Mar 22, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. -

Mar 17, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2014

Pathway Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Jul 29, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 10, 2019

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 05, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Breast and/or ovarian cancer Uncertain:1

Jul 20, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MSH2-related disorder Uncertain:1

Sep 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 c.2732T>G variant is predicted to result in the amino acid substitution p.Leu911Arg. This variant has been previously reported in individuals with colorectal cancer (Barnetson et al. 2008. PubMed ID: 18033691; Table S1, Raskin et al. 2017. PubMed ID: 29212164), endometrial cancer (Singh et al. 2020. PubMed ID: 32634176), and ovarian cancer (Pal et al. 2012. PubMed ID: 23047549). Functional studies did not support the pathogenicity of this variant (Figure S7, Houlleberghs et al. 2016. PubMed ID: 26951660; LOF score <0 in Table S4, Jia et al. 2021. PubMed ID: 33357406). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/91039/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Carcinoma of colon 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.Leu911Arg variant was identified in 2 of 5650 proband chromosomes (frequency: 0.0004) from individuals or families with lynch syndrome or ovarian cancer and was identified in 1 of 1140 control chromosomes (freq: 0.001), from healthy individuals (Barnetson 2008, Pal 2012, Karageorgos 2015). The variant was also identified in dbSNP (ID: rs41295182) as "With other allele ", ClinVar (classified as uncertain significance by Invitae, GeneDx, Pathway Genomics, Counsyl, InSight and two clinical laboratories; as likely benign by Ambry Genetics), Clinvitae, MutDB, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors (6x class3). The variant was not identified in the COGR, Cosmic, UMD-LSDB, or Zhejiang University databases. The variant was identified in control databases in 17 of 275962 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23976 chromosomes (freq: 0.00004), European in 16 of 126192 chromosomes (freq: 0.0001); but not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu911 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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. -

Lynch syndrome Uncertain:1

Dec 02, 2020

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.2732T>G (p.Leu911Arg) missense change has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-47710015-T-G). Six of seven in silico tools predict a damaging effect of this variant on protein function (PP3). However, a functional assay demonstrated that this variant did not result in 6TG-resistant colony formation, an indicator of mismatch repair activity, suggesting a likely benign effect (PMID: 26951660). This variant has been identified in at least four individuals with colon cancer (PMID: 12537652, 18033691, 23047549, 28125075, 29212164), one individual with endometrial cancer (PMID: 32634176), one individual with epithelial ovarian cancer (PMID: 23047549). In one of these studies, the variant did not segregate with the cancer phenotype within the proband’s family (PMID: 18033691). Another report indicates the presence of the variant in 7 individuals in a cancer-free pedigree on both sides of the family with no mention of consanguinity (https://pubmed.ncbi.nlm.nih.gov/26092435/). In summary, this variant meets criteria to be classified as 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.97	D;.
Vest4		0.91
MVP		0.91
MPC		0.027
ClinPred		0.80	D
GERP RS		5.4
Varity_R		0.87
gMVP		0.78

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: rs41295182; hg19: chr2-47710015;