Genetic Variant MSH2:p.Arg308Ile (chr2-47414399-G-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000251.3(MSH2):c.923G>T(p.Arg308Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R308T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.38

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 20 benign, 38 uncertain in NM_000251.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.923G>T	p.Arg308Ile	missense_variant	Exon 5 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.923G>T	p.Arg308Ile	missense_variant	Exon 5 of 16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1072424

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

539982

African (AFR)

AF:

0.00

AC:

AN:

25038

American (AMR)

AF:

0.00

AC:

AN:

38480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18542

East Asian (EAS)

AF:

0.00

AC:

AN:

25402

South Asian (SAS)

AF:

0.00

AC:

AN:

77220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41658

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3662

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

800200

Other (OTH)

AF:

0.00

AC:

AN:

42222

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

D;.;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Uncertain

2.8

M;.;.;.

PhyloP100

4.4

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.3

D;D;.;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0030

D;D;.;D

Sift4G

Uncertain

0.0080

D;D;.;D

Polyphen

0.73

P;.;.;P

Vest4

0.68

MutPred

0.76

Gain of stability (P = 0.0159);.;Gain of stability (P = 0.0159);Gain of stability (P = 0.0159);

MVP

0.94

MPC

0.021

ClinPred

0.99

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.35

Mutation Taster

=54/46

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

Computational scores

Splicing

Publications

Other links and lift over