dbSNP rs4987188: MSH2:p.Gly322Asp (chr2-47416318-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000251.3(MSH2):c.965G>A(p.Gly322Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0145 in 1,612,018 control chromosomes in the GnomAD database, including 240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G322S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 22 hom., cov: 32)

Exomes 𝑓: 0.015 ( 218 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:32O:1

Conservation

PhyloP100: 4.65

Publications

115 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: ClinGen, Orphanet, G2P
Lynch syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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: G2P, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 22 benign, 30 uncertain in NM_000251.3

BP4

Computational evidence support a benign effect (MetaRNN=0.009123743).

BP6

Variant 2-47416318-G-A is Benign according to our data. Variant chr2-47416318-G-A is described in ClinVar as Benign. ClinVar VariationId is 1762.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0124 (1885/152188) while in subpopulation NFE AF = 0.0173 (1175/68008). AF 95% confidence interval is 0.0165. There are 22 homozygotes in GnomAd4. There are 981 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MSH2	NM_000251.3	MANE Select	c.965G>A	p.Gly322Asp	missense	Exon 6 of 16	NP_000242.1	P43246-1
MSH2	NM_001406674.1		c.965G>A	p.Gly322Asp	missense	Exon 6 of 18	NP_001393603.1
MSH2	NM_001406631.1		c.965G>A	p.Gly322Asp	missense	Exon 6 of 18	NP_001393560.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MSH2	ENST00000233146.7	TSL:1 MANE Select	c.965G>A	p.Gly322Asp	missense	Exon 6 of 16	ENSP00000233146.2	P43246-1
MSH2	ENST00000406134.5	TSL:1	c.965G>A	p.Gly322Asp	missense	Exon 6 of 16	ENSP00000384199.1	E9PHA6
MSH2	ENST00000918107.1		c.1016G>A	p.Gly339Asp	missense	Exon 7 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes

AF:

0.0124

AC:

1889

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.00787

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00769

Gnomad FIN

AF:

0.0319

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0134

AC:

3375

AN:

251428

AF XY:

0.0134

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00598

Gnomad ASJ exome

AF:

0.0220

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0310

Gnomad NFE exome

AF:

0.0171

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.0147

AC:

21504

AN:

1459830

Hom.:

218

Cov.:

AF XY:

0.0146

AC XY:

10590

AN XY:

726418

show subpopulations

African (AFR)

AF:

0.00203

AC:

AN:

33446

American (AMR)

AF:

0.00615

AC:

275

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0219

AC:

573

AN:

26116

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39672

South Asian (SAS)

AF:

0.00664

AC:

572

AN:

86206

European-Finnish (FIN)

AF:

0.0295

AC:

1573

AN:

53412

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0158

AC:

17579

AN:

1110142

Other (OTH)

AF:

0.0135

AC:

813

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

953

1907

2860

3814

4767

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

612

1224

1836

2448

3060

<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

AF:

0.0124

AC:

1885

AN:

152188

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

981

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00229

AC:

AN:

41540

American (AMR)

AF:

0.00786

AC:

120

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00769

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0319

AC:

338

AN:

10590

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0173

AC:

1175

AN:

68008

Other (OTH)

AF:

0.0133

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

196

293

391

489

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0145

Hom.:

Bravo

AF:

0.00931

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0153

AC:

132

ExAC

AF:

0.0141

AC:

1709

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0162

EpiControl

AF:

0.0140

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lynch syndrome 1 (8)

not specified (9)

Hereditary cancer-predisposing syndrome (6)

Lynch syndrome (3)

not provided (3)

Breast carcinoma (1)

Carcinoma of colon (1)

Hereditary nonpolyposis colorectal neoplasms (1)

MSH2 POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0091

MetaSVM

Uncertain

0.093

MutationAssessor

Uncertain

2.2

PhyloP100

4.6

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.56

Sift

Benign

0.13

Sift4G

Benign

0.25

Polyphen

0.43

Vest4

0.18

MPC

0.0063

ClinPred

0.016

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.26

gMVP

0.34

Mutation Taster

=84/16

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over