Variant NM_000251.3:c.942+28_942+29delAA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1

The NM_000251.3(MSH2):c.942+28_942+29delAA variant causes a intron change. The variant allele was found at a frequency of 0.179 in 965,430 control chromosomes in the GnomAD database, including 1,339 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.16 ( 371 hom., cov: 0)

Exomes 𝑓: 0.18 ( 1339 hom. )

Failed GnomAD Quality Control

Consequence

MSH2
NM_000251.3 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 6.75

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 2-47414420-TAA-T is Benign according to our data. Variant chr2-47414420-TAA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 336427.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=4, Likely_benign=2}. Variant chr2-47414420-TAA-T is described in Lovd as [Benign]. Variant chr2-47414420-TAA-T is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.942+28_942+29delAA		intron_variant	Intron 5 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.942+3_942+4delAA		splice_region_variant, intron_variant	Intron 5 of 15	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

9816

AN:

62568

Hom.:

372

Cov.:

FAILED QC

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.256

Gnomad AMR

AF:

0.163

Gnomad ASJ

AF:

0.192

Gnomad EAS

AF:

0.217

Gnomad SAS

AF:

0.252

Gnomad FIN

AF:

0.200

Gnomad MID

AF:

0.265

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.162

GnomAD3 exomes

AF:

0.0914

AC:

4790

AN:

52420

Hom.:

AF XY:

0.0872

AC XY:

2450

AN XY:

28096

show subpopulations

Gnomad AFR exome

AF:

0.0887

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.0905

Gnomad EAS exome

AF:

0.116

Gnomad SAS exome

AF:

0.0818

Gnomad FIN exome

AF:

0.0335

Gnomad NFE exome

AF:

0.0841

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.179

AC:

173109

AN:

965430

Hom.:

1339

AF XY:

0.176

AC XY:

84578

AN XY:

479320

show subpopulations

Gnomad4 AFR exome

AF:

0.149

Gnomad4 AMR exome

AF:

0.125

Gnomad4 ASJ exome

AF:

0.152

Gnomad4 EAS exome

AF:

0.177

Gnomad4 SAS exome

AF:

0.140

Gnomad4 FIN exome

AF:

0.149

Gnomad4 NFE exome

AF:

0.186

Gnomad4 OTH exome

AF:

0.175

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.157

AC:

9812

AN:

62570

Hom.:

371

Cov.:

AF XY:

0.160

AC XY:

4436

AN XY:

27718

show subpopulations

Gnomad4 AFR

AF:

0.161

Gnomad4 AMR

AF:

0.163

Gnomad4 ASJ

AF:

0.192

Gnomad4 EAS

AF:

0.215

Gnomad4 SAS

AF:

0.251

Gnomad4 FIN

AF:

0.200

Gnomad4 NFE

AF:

0.142

Gnomad4 OTH

AF:

0.160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome

Uncertain:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1

Uncertain:1Benign:1

Jun 04, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MSH2-related disorder

Benign:1

Apr 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Breast and/or ovarian cancer

Benign:1

Jul 06, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Aug 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Mar 22, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over