2-47478327-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM1PM2PM5PP3_StrongBP6

The NM_000251.3(MSH2):c.2266A>G(p.Thr756Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,772 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T756P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 8.69

Publications

0 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_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 27 uncertain in NM_000251.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

BP6

Variant 2-47478327-A-G is Benign according to our data. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790. Variant chr2-47478327-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 479790.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.2266A>G	p.Thr756Ala	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.2266A>G	p.Thr756Ala	missense_variant	Exon 14 of 16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251420

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727186

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111936

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome

Uncertain:1

Jan 11, 2024

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

May 17, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Nov 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T756A variant (also known as c.2266A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2266. The threonine at codon 756 is replaced by alanine, an amino acid with similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Jan 11, 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.5

H;.;.;.

PhyloP100

8.7

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.7

D;D;.;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Uncertain

0.0040

D;D;.;D

Polyphen

1.0

D;.;.;D

Vest4

0.98

MutPred

0.94

Loss of phosphorylation at T756 (P = 0.0751);.;Loss of phosphorylation at T756 (P = 0.0751);Loss of phosphorylation at T756 (P = 0.0751);

MVP

0.95

MPC

0.035

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.94

Mutation Taster

=15/85

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over