rs63751618

Positions:

• chr2-47480865-AAG-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.2633_2634delAG​(p.Glu878fs) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E878E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 frameshift, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 5.18

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47480865-AAG-A is Pathogenic according to our data. Variant chr2-47480865-AAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 91015.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47480865-AAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2633_2634delAG	p.Glu878fs	frameshift_variant, splice_region_variant	15/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2633_2634delAG	p.Glu878fs	frameshift_variant, splice_region_variant	15/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2017	This deletion of two nucleotides in MSH2 is denoted c.2633_2634delAG at the cDNA level and p.Glu878AlafsX3 (E878AfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGAG[delAG]GTTT. The deletion causes a frameshift which changes a Glutamic Acid to an Alanine at codon 878, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. MSH2 c.2633_2634delAG, also published as 2629delAG using alternate nomenclature, has been observed in many families presenting with a Lynch syndrome phenotype (Miyaki 1995, Yuan 1998, Millar 1999, Durno 2005) while tumor testing has consistently shown microsatellite instability (MSI-H) and loss of the MSH2 protein via immunohistochemistry (Konishi 1996, Marcus 1999, Millar 1999, Terdiman 2001, Rubio 2016). Additionally, using mouse embryonic stem cells, Wielders et al. (2017) found that MSH2 variants lacking the c-terminus severely destabilize MSH2/MSH6 interaction and result in increased microsatellite instability. We consider this variant to be pathogenic. -

Lynch syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 09, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Lynch syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation introducing premature termination codon -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2016	Variant summary: The MSH2 c.2633_2634delAG (p.Glu878Alafs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.2653C>T (p.Gln885X)). The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals. In addition, multiple clinical diagnostic laboratories and databases have cited the variant as "Causal/Pathogenic." Therefore, the variant of interest has been classified as "Pathogenic." -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 24, 2022	The c.2633_2634delAG pathogenic mutation, located in coding exon 15 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 2633 to 2634, causing a translational frameshift with a predicted alternate stop codon (p.E878Afs*3). This mutation has previously been identified in multiple families and individuals affected with colorectal and/or endometrial cancer (Rubio I et al. Oncology. 2016 Jul;91:171-6; Durno C et al. Gut. 2005 Aug;54:1146-50; Shin YK et al. Hum. Mutat. 2004 Oct;24:351; Terdiman JP et al. Gastroenterology. 2001 Jan;120:21-30; Millar AL et. al. Hum. Mol. Genet. 1999 May;8:823-9; Miyaki M et al. J. Mol. Med. 1995 Oct;73:515-20). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2023	This variant deletes 2 nucleotides in exon 15 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome, as well as individuals affected with colorectal cancer or endometrial cancer (PMID: 8581513, 9559627, 10196371, 11208710, 15845562, 22890886, 22949379, 26485756, 27398995). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 11, 2018

The MSH2 c.2633_2634delAG; p.Glu878fs variant, is reported in the literature in multiple individuals and families affected with Lynch syndrome, colorectal cancer, endometrial cancer, or breast cancer (Bapat 1999, Durno 2005, Millar 1999, Miyaki 1995, Rubio 2016, Shin 2004, Sun 2017). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 91015), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 2 nucleotides, resulting in a premature termination codon in the last exon of the MSH2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein. Functional analyses of the variant protein have identified a truncated protein product (Bapat 1999), and a mouse model shows phenotypes reminiscent of Lynch syndrome (Wielders 2017). Based on available information, the p.Glu878fs variant is considered to be pathogenic. References Bapat BV et al. Family history characteristics, tumor microsatellite instability and germline MSH2 and MLH1 mutations in hereditary colorectal cancer. Hum Genet. 1999 Feb;104(2):167-76. Durno C et al. Family history and molecular features of children, adolescents, and young adults with colorectal carcinoma. Gut. 2005 Aug;54(8):1146-50. Millar AL et al. Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium. Hum Mol Genet. 1999 May;8(5):823-9. Miyaki M et al. Germ line mutations of hMSH2 and hMLH1 genes in Japanese families with hereditary nonpolyposis colorectal cancer (HNPCC): usefulness of DNA analysis for screening and diagnosis of HNPCC patients. J Mol Med (Berl). 1995 Oct;73(10):515-20. Rubio I et al. Analysis of Lynch Syndrome Mismatch Repair Genes in Women with Endometrial Cancer. Oncology. 2016;91(3):171-6. Shin YK et al. Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-polyposis colorectal cancer families. Hum Mutat. 2004 Oct;24(4):351. Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. Wielders E et al. Truncation of the MSH2 C-terminal 60 amino acids disrupts effective DNA mismatch repair and is causative for Lynch syndrome. Fam Cancer. 2017 Apr;16(2):221-229. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Ile883Leufs*9) have been determined to be pathogenic (PMID: 11579115, 14970868). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MSH2 function (PMID: 18781619). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 91015). This premature translational stop signal has been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 8581513, 10196371, 15365995, 15845562, 27398995). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu878Alafs*3) in the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the MSH2 protein. -

Computational scores

Source: dbNSFP v4.3

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: rs63751618; hg19: chr2-47708004;