NM_000251.3:c.940C>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM5

The NM_000251.3(MSH2):c.940C>A(p.Gln314Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. Q314P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., cov: 14)

Exomes 𝑓: 0.00021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MSH2
NM_000251.3 missense, splice_region

Scores

Splicing: ADA: 0.8088

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.59

Publications

8 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 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 28 benign, 37 uncertain in NM_000251.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-47414418-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 483693.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.940C>A	p.Gln314Lys	missense_variant, splice_region_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.940C>A	p.Gln314Lys	missense_variant, splice_region_variant	Exon 5 of 16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000442

AC:

AN:

45208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000914

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000373

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

125796

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000210

AC:

AN:

438710

Hom.:

Cov.:

AF XY:

0.000191

AC XY:

AN XY:

230554

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:

10904

American (AMR)

AF:

0.000157

AC:

AN:

19050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10200

East Asian (EAS)

AF:

0.000217

AC:

AN:

13850

South Asian (SAS)

AF:

0.0000706

AC:

AN:

42480

European-Finnish (FIN)

AF:

0.0000398

AC:

AN:

25106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1322

European-Non Finnish (NFE)

AF:

0.000255

AC:

AN:

297824

Other (OTH)

AF:

0.000334

AC:

AN:

17974

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.239

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000442

AC:

AN:

45234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

19878

show subpopulations

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

African (AFR)

AF:

0.0000913

AC:

AN:

10956

American (AMR)

AF:

0.00

AC:

AN:

2330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1532

East Asian (EAS)

AF:

0.00

AC:

AN:

1424

South Asian (SAS)

AF:

0.00

AC:

AN:

892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000373

AC:

AN:

26840

Other (OTH)

AF:

0.00

AC:

AN:

456

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000983081), 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

Genome 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;.;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.74

D;D;D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Benign

2.0

M;.;.;.

PhyloP100

7.6

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.98

N;N;.;N

REVEL

Pathogenic

0.77

Sift

Uncertain

0.015

D;D;.;D

Sift4G

Uncertain

0.034

D;D;.;D

Polyphen

0.27

B;.;.;P

Vest4

0.80

MutPred

0.58

Gain of ubiquitination at Q314 (P = 0.0238);.;Gain of ubiquitination at Q314 (P = 0.0238);Gain of ubiquitination at Q314 (P = 0.0238);

MVP

0.96

MPC

0.013

ClinPred

0.96

GERP RS

5.0

Varity_R

0.51

gMVP

0.39

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.81

dbscSNV1_RF

Pathogenic

0.78

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over