Genetic Variant MSH2:c.942+26_942+29delAAAA (chr2-47414420-TAAAA-T) – ACMG Classification: Benign (-9 pts)

Variant summary

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

The ENST00000233146.7(MSH2):c.942+3_942+6delAAAA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0838 in 1,004,160 control chromosomes in the GnomAD database, including 56 homozygotes. 1/1 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 0.0071 ( 3 hom., cov: 0)

Exomes 𝑓: 0.089 ( 53 hom. )

Consequence

MSH2
ENST00000233146.7 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 2-47414420-TAAAA-T is Benign according to our data. Variant chr2-47414420-TAAAA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 336428.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=7, Uncertain_significance=1}. Variant chr2-47414420-TAAAA-T is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.942+26_942+29delAAAA		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+6delAAAA		splice_region_variant, intron_variant	Intron 5 of 15	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.00710

AC:

442

AN:

62230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00218

Gnomad ASJ

AF:

0.00170

Gnomad EAS

AF:

0.000612

Gnomad SAS

AF:

0.00451

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.00514

GnomAD3 exomes

AF:

0.0847

AC:

4442

AN:

52420

Hom.:

AF XY:

0.0830

AC XY:

2331

AN XY:

28096

show subpopulations

Gnomad AFR exome

AF:

0.0800

Gnomad AMR exome

AF:

0.115

Gnomad ASJ exome

AF:

0.0705

Gnomad EAS exome

AF:

0.111

Gnomad SAS exome

AF:

0.0841

Gnomad FIN exome

AF:

0.0348

Gnomad NFE exome

AF:

0.0738

Gnomad OTH exome

AF:

0.110

GnomAD4 exome

AF:

0.0889

AC:

83751

AN:

941928

Hom.:

AF XY:

0.0903

AC XY:

42096

AN XY:

466340

show subpopulations

Gnomad4 AFR exome

AF:

0.0906

Gnomad4 AMR exome

AF:

0.104

Gnomad4 ASJ exome

AF:

0.0945

Gnomad4 EAS exome

AF:

0.120

Gnomad4 SAS exome

AF:

0.0957

Gnomad4 FIN exome

AF:

0.112

Gnomad4 NFE exome

AF:

0.0861

Gnomad4 OTH exome

AF:

0.0943

GnomAD4 genome

AF:

0.00709

AC:

441

AN:

62232

Hom.:

Cov.:

AF XY:

0.00714

AC XY:

197

AN XY:

27576

show subpopulations

Gnomad4 AFR

AF:

0.0207

Gnomad4 AMR

AF:

0.00217

Gnomad4 ASJ

AF:

0.00170

Gnomad4 EAS

AF:

0.000612

Gnomad4 SAS

AF:

0.00453

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.00513

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

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

- -

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome

Uncertain:1Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Jul 10, 2020

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. -

Jan 27, 2022

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided

Benign:1

Aug 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast carcinoma

Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as compound heterozygous. -

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.

2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAA

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