dbSNP rs2303425: MSH2:c.-132T>C (chr2-47403074-T-C) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001258281.1(MSH2):c.-132T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 985,838 control chromosomes in the GnomAD database, including 8,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.10 ( 1088 hom., cov: 33)

Exomes 𝑓: 0.13 ( 7239 hom. )

Consequence

MSH2
NM_001258281.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: 1.90

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 2-47403074-T-C is Benign according to our data. Variant chr2-47403074-T-C is described in ClinVar as [Benign]. Clinvar id is 90485.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47403074-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.-118T>C		upstream_gene_variant		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.-118T>C		upstream_gene_variant		1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15784

AN:

151944

Hom.:

1090

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0265

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.142

Gnomad ASJ

AF:

0.0599

Gnomad EAS

AF:

0.181

Gnomad SAS

AF:

0.0632

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.106

GnomAD4 exome

AF:

0.126

AC:

105018

AN:

833776

Hom.:

7239

Cov.:

AF XY:

0.123

AC XY:

53236

AN XY:

431420

show subpopulations

Gnomad4 AFR exome

AF:

0.0217

Gnomad4 AMR exome

AF:

0.148

Gnomad4 ASJ exome

AF:

0.0643

Gnomad4 EAS exome

AF:

0.161

Gnomad4 SAS exome

AF:

0.0556

Gnomad4 FIN exome

AF:

0.147

Gnomad4 NFE exome

AF:

0.137

Gnomad4 OTH exome

AF:

0.117

GnomAD4 genome

AF:

0.104

AC:

15783

AN:

152062

Hom.:

1088

Cov.:

AF XY:

0.105

AC XY:

7819

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0264

Gnomad4 AMR

AF:

0.143

Gnomad4 ASJ

AF:

0.0599

Gnomad4 EAS

AF:

0.180

Gnomad4 SAS

AF:

0.0639

Gnomad4 FIN

AF:

0.153

Gnomad4 NFE

AF:

0.133

Gnomad4 OTH

AF:

0.105

Alfa

AF:

0.126

Hom.:

175

Bravo

AF:

0.101

Asia WGS

AF:

0.116

AC:

404

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Lynch syndrome 1

Benign:3

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26975740) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Nov 05, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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 19, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome

Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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

-0.28

CADD

Benign

DANN

Benign

0.94

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