chr2-47478436-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The NM_000251.3(MSH2):c.2375A>G(p.Asn792Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. N792D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 1.34

Publications

3 publications found

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 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

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 18 benign, 35 uncertain in NM_000251.3

BP4

Computational evidence support a benign effect (MetaRNN=0.08263704).

BP6

Variant 2-47478436-A-G is Benign according to our data. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010. Variant chr2-47478436-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 143010.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.2375A>G	p.Asn792Ser	missense_variant	Exon 14 of 16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.2375A>G	p.Asn792Ser	missense_variant	Exon 14 of 16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251434

AF XY:

0.0000294

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.000197

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 1

Uncertain:3

Mar 01, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 27, 2016

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. -

Mar 20, 2023

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Nov 11, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Nov 04, 2020

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces asparagine with serine at codon 792 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251434 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Mar 13, 2019

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome

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.Asn792Ser variant was not identified in the literature nor was it identified in Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs587782891, With Uncertain significance allele) and ClinVar (four times as a variant of uncertain significance). The variant was identified in control databases in 4 of 246206 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017) with population frequencies as follows: South Asian in 4 of 30782 chromosomes (freq: 0.0001); and was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asn792 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and only 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not reliably 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. -

not provided

Uncertain:1

Oct 31, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24362816, 36243179, 18822302, 21120944, 31784482) -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;.;.;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.0051

MetaRNN

Benign

0.083

T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

-0.14

N;.;.;.

PhyloP100

1.3

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.80

N;N;.;N

REVEL

Uncertain

0.30

Sift

Benign

0.13

T;T;.;T

Sift4G

Benign

0.13

T;T;.;T

Polyphen

0.0

B;.;.;B

Vest4

0.21

MutPred

0.37

Gain of glycosylation at N792 (P = 0.0342);.;Gain of glycosylation at N792 (P = 0.0342);Gain of glycosylation at N792 (P = 0.0342);

MVP

0.86

MPC

0.0069

ClinPred

0.090

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.065

gMVP

0.32

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over