rs63751099

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000251.3(MSH2):c.28C>A(p.Gln10Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q10H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.96

Publications

6 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20983204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.28C>A	p.Gln10Lys	missense_variant	Exon 1 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.28C>A	p.Gln10Lys	missense_variant	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1448258

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719316

African (AFR)

AF:

0.00

AC:

AN:

33334

American (AMR)

AF:

0.00

AC:

AN:

42546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25804

East Asian (EAS)

AF:

0.00

AC:

AN:

39232

South Asian (SAS)

AF:

0.00

AC:

AN:

84018

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106904

Other (OTH)

AF:

0.00

AC:

AN:

59856

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Mar 25, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Q10K variant (also known as c.28C>A), located in coding exon 1 of the MSH2 gene, results from a C to A substitution at nucleotide position 28. The glutamine at codon 10 is replaced by lysine, an amino acid with similar properties. This variant was detected as a secondary finding in 1 out of 186 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am J Hum Genet, 2012 Jul;91:97-108). This alteration has also been identified in a cohort of 572 atherosclerosis patients with no clinical history of cancer (Pinard A et al. Hum Mutat, 2016 12;37:1299-1307). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

T;.;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.035

N;.;.

PhyloP100

2.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.37

N;.;N

REVEL

Uncertain

0.45

Sift

Benign

0.36

T;.;T

Sift4G

Benign

0.78

T;.;T

Polyphen

0.017

B;.;B

Vest4

0.38

MutPred

0.35

Gain of ubiquitination at Q10 (P = 0.0203);Gain of ubiquitination at Q10 (P = 0.0203);Gain of ubiquitination at Q10 (P = 0.0203);

MVP

0.97

MPC

0.0061

ClinPred

0.28

GERP RS

3.6

PromoterAI

-0.080

Neutral

(source)

Varity_R

0.35

gMVP

0.41

Mutation Taster

=88/12

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

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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