Variant chr2-47482876-T-G details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.2732T>G	p.Leu911Arg	missense_variant	16/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.2732T>G	p.Leu911Arg	missense_variant	16/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

9

AN:

152192

Hom.:

0

Cov.:

33

show subpopulations

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

show subpopulations

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

show subpopulations

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

show subpopulations

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:11Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 14, 2023	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. -

Lynch syndrome 1

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Pathway Genomics	Oct 30, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 17, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 22, 2023	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. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 10, 2019	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 05, 2022	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2020	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 23, 2022	This variant has not been described in online databases. The frequency of this variant in the general population, 0.00013 (17/128602 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported 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)). 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. -

MSH2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2024

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

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 20, 2021

- -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 02, 2020

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 probandâ€™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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

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;.

MutationTaster

Benign

1.0

D;D;D

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

Below is the list of publications found by LitVar. It may be empty.

chr2-47482876-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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