NM_000251.3:c.212-3A>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000251.3(MSH2):c.212-3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,582,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MSH2
NM_000251.3 splice_region, intron

Scores

Splicing: ADA: 0.001555

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.177

Publications

1 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_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 2-47408398-A-T is Benign according to our data. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472. Variant chr2-47408398-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 252472.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.212-3A>T		splice_region_variant, intron_variant	Intron 1 of 15	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.212-3A>T		splice_region_variant, intron_variant	Intron 1 of 15	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

150126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000171

AC:

AN:

234352

AF XY:

0.0000157

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000129

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

AF:

0.0000105

AC:

AN:

1432424

Hom.:

Cov.:

AF XY:

0.00000981

AC XY:

AN XY:

713268

show subpopulations

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

African (AFR)

AF:

0.0000315

AC:

AN:

31720

American (AMR)

AF:

0.000199

AC:

AN:

40296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25402

East Asian (EAS)

AF:

0.00

AC:

AN:

39400

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5542

European-Non Finnish (NFE)

AF:

0.00000365

AC:

AN:

1095854

Other (OTH)

AF:

0.0000169

AC:

AN:

59076

⚠️ 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: 0.295

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

AF:

0.0000200

AC:

AN:

150126

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40864

American (AMR)

AF:

0.000198

AC:

AN:

15120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67594

Other (OTH)

AF:

0.00

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome

Uncertain:1Benign:1

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 09, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Aug 23, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

May 10, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

MSH2-related disorder

Benign:1

Aug 01, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

May 14, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

0.18

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0016

dbscSNV1_RF

Benign

0.058

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