rs750646335

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000251.3(MSH2):c.2266A>C(p.Thr756Pro) 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. T756S) has been classified as Likely benign.

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 P:2U: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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 2-47478327-A-C is Pathogenic according to our data. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172. Variant chr2-47478327-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1008172.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.2266A>C	p.Thr756Pro	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>C	p.Thr756Pro	missense_variant	Exon 14 of 16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00

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:

8.99e-7

AC:

AN:

1111936

Other (OTH)

AF:

0.00

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: 0.275

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: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 1

Pathogenic:2

Aug 08, 2023

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Sep 25, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Sep 01, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. This variant has not been reported in the literature in individuals with MSH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with proline at codon 756 of the MSH2 protein (p.Thr756Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.2

M;.;.;.

PhyloP100

8.7

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.6

D;D;.;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Uncertain

0.0020

D;D;.;D

Polyphen

1.0

D;.;.;D

Vest4

0.89

MutPred

0.92

Loss of catalytic residue at T756 (P = 0.0519);.;Loss of catalytic residue at T756 (P = 0.0519);Loss of catalytic residue at T756 (P = 0.0519);

MVP

0.94

MPC

0.032

ClinPred

1.0

GERP RS

5.0

Varity_R

0.98

gMVP

0.98

Mutation Taster

=8/92

disease causing

(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

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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