rs2303425

Positions:

• chr2-47403074-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001258281.1(MSH2):​c.-132T>C variant causes a 5 prime UTR 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
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: 1.90

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]

ACMG classification

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/exons	MANE	Protein	UniProt
MSH2	NM_001258281.1	c.-132T>C		5_prime_UTR_variant	1/17		NP_001245210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000543555.6	c.-132T>C		5_prime_UTR_variant	1/17	2		ENSP00000442697
MSH2	ENST00000645506.1			upstream_gene_variant				ENSP00000495455
MSH2	ENST00000644092.1			upstream_gene_variant				ENSP00000496351

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15784 AN: 151944 Hom.: 1090 Cov.: 33

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.: 12 AF XY: 0.123 AC XY: 53236 AN XY: 431420

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.: 33 AF XY: 0.105 AC XY: 7819 AN XY: 74306

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

Submissions by phenotype

Lynch syndrome 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26975740) -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 05, 2014	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
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

Other links and lift over

dbSNP: rs2303425; hg19: chr2-47630213; COSMIC: COSV51880314; COSMIC: COSV51880314;