chr2-47429882-G-A

Position:

chr2-47429882-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The NM_000251.3(MSH2):c.1217G>A(p.Arg406Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000576 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R406L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:8

Conservation

PhyloP100: 6.03

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 14 uncertain in NM_000251.3

BP4

Computational evidence support a benign effect (MetaRNN=0.14374474).

BP6

Variant 2-47429882-G-A is Benign according to our data. Variant chr2-47429882-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90569.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=5, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1217G>A	p.Arg406Gln	missense_variant	7/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.1217G>A	p.Arg406Gln	missense_variant	7/16	1	NM_000251.3	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00231

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

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251406

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00176

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152012

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 1

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 08, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 23, 2023	This variant is considered benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 11, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 01, 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. -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 01, 2024	Variant summary: MSH2 c.1217G>A (p.Arg406Gln) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-05 in 1613794 control chromosomes (gnomAD), predominantly at a frequency of 0.002 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. To our knowledge, c.1217G>A has not been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating an impact on protein function has been reported. A recent case-control study showed that this variant was not associated with breast cancer (Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36845387, 33471991, 26333163). ClinVar contains an entry for this variant (Variation ID: 90569). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 11, 2020	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1217G>A, in exon 7 that results in an amino acid change, p.Arg406Gln. This sequence change does not appear to have been previously described in patients with MSH2-related disorders and has been described in the EXAC database with a low population frequency of 0.19% in the Ashkenazi Jewish subpopulation (dbSNP rs146567853). The p.Arg406Gln change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg406Gln substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg406Gln change remains unknown at this time. -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2018	This variant is denoted MSH2 c.1217G>A at the cDNA level, p.Arg406Gln (R406Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been observed in an individual with a history of a single sebaceous adenoma showing loss of MSH2 (Thompson 2014), and in at least one individual with advanced cancer of unspecified type (Mandelker 2017). MSH2 Arg406Gln was observed at an allele frequency of 0.2% (20/10,146) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located within the Lever domain and in the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain due to insufficient evidence (Thompson 2014). Based on currently available evidence, it is unclear whether MSH2 Arg406Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH2 p.Arg406Gln variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from individuals or families with advanced cancer, type not specified (Mandelker 2017). The variant was also identified in dbSNP (ID: rs146567853) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics and Invitae; and as uncertain significance by GeneDx, Counsyl, Fulgent, and InSiGHT), and COSMIC databases (confirmed somatic in adenocarcinoma of the large intestine). The variant was not identified in GeneInsight-COGR, MutDB, Mismatch Repair Genes Variant Database, or UMD-LSDB databases. The variant was identified in control databases in 24 of 277084 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 20 of 10146 chromosomes (freq: 0.002, increasing the likelihood this could be a low frequency benign variant), Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 2 of 34418 chromosomes (freq: 0.00006), and European Non-Finnish in 1 of 126604 chromosomes (freq: 0.000008), while the variant was not observed in the African, East Asian, European Finnish, or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg406 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. 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. -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 02, 2022

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

D;.;.;.

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Benign

0.049

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.5

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.8

D;D;.;D

REVEL

Pathogenic

0.69

Sift

Benign

0.049

D;D;.;D

Sift4G

Uncertain

0.040

D;D;.;D

Polyphen

0.067

B;.;.;B

Vest4

0.49

MVP

0.96

MPC

0.0065

ClinPred

0.24

GERP RS

4.6

Varity_R

0.65

gMVP

0.59

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over