chr2-47475093-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM5BP4BP6

The NM_000251.3(MSH2):c.1828C>T(p.His610Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,834 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. H610Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 1.38

Publications

5 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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 26 benign, 30 uncertain in NM_000251.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-47475094-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 1780893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.331011).

BP6

Variant 2-47475093-C-T is Benign according to our data. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308. Variant chr2-47475093-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 184308.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.1828C>T	p.His610Tyr	missense_variant	Exon 12 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.1828C>T	p.His610Tyr	missense_variant	Exon 12 of 16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727220

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:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

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

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Jun 29, 2022

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. -

Nov 09, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces histidine with tyrosine at codon 610 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.1829A>C (p.His610Pro), is considered to be disease-causing (ClinVar variation ID: 1780893), suggesting that this position may be important for the protein function. 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

Nov 18, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome 1

Uncertain:1

Oct 04, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome

Uncertain:1

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Dec 31, 2024

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 has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: exhibits sensitivity to 6-TG and mismatch repair (MMR) function similar to wild-type (PMID: 33357406); This variant is associated with the following publications: (PMID: 18822302, 9774676, 21120944, 36550560, 33357406, 33850299) -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Oct 27, 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

0.089

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;.;.;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.065

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.85

T;D;T;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.33

T;T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.9

L;.;.;.

PhyloP100

1.4

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.6

D;D;.;D

REVEL

Uncertain

0.43

Sift

Benign

0.17

T;T;.;T

Sift4G

Benign

1.0

T;T;.;T

Polyphen

0.0010

B;.;.;B

Vest4

0.48

MutPred

0.55

Gain of phosphorylation at H610 (P = 0.0926);.;Gain of phosphorylation at H610 (P = 0.0926);Gain of phosphorylation at H610 (P = 0.0926);

MVP

0.91

MPC

0.0064

ClinPred

0.38

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.69

Mutation Taster

=83/17

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over