2-47414283-ACTGT-A

Position:

• chr2-47414283-ACTGT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.811_814delTCTG​(p.Ser271fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 29)
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 6.01

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47414283-ACTGT-A is Pathogenic according to our data. Variant chr2-47414283-ACTGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 91222.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47414283-ACTGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.811_814delTCTG	p.Ser271fs	frameshift_variant	5/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.811_814delTCTG	p.Ser271fs	frameshift_variant	5/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 29

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

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 21, 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	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 19, 2024	- -

Lynch syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2017	Variant summary: The MSH2 c.811_814delTCTG (p.Ser271Argfs) 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. This variant is absent in 121074 control chromosomes. Multiple publications have cited the variant in affected individuals and observed loss of MSH2 protein expression. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, 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

Aug 31, 2018

The MSH2 c.811_814del; p.Ser271fs variant (also known as 808delGTCT) is reported in the medical literature in at least two individuals that fulfilled diagnostic criteria for HNPCC (Ewald 2007, Farrington 1998, Lagerstedt 2007, Liu 1995). The variant is described in the ClinVar database (Variation ID: 91222), in the dbSNP variant database (rs587779185), but is not listed in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The variant deletes four nucleotides, creates a frameshift and is predicted to result in a truncated protein or mRNA subject to non-sense mediated decay. Considering available information, this variant is classified as pathogenic. References Ewald J et al. Immunohistochemical staining for mismatch repair proteins, and its relevance in the diagnosis of hereditary non-polyposis colorectal cancer. Br J Surg. 2007 Aug;94(8):1020-7. Farrington SM et al. Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls. Am J Hum Genet. 1998 Sep;63(3):749-59. Lagerstedt Robinson K et al. Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. J Natl Cancer Inst. 2007 Feb 21;99(4):291-9. Liu B et al. Genetic instability occurs in the majority of young patients with colorectal cancer. Nat Med. 1995 Apr;1(4):348-52. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Sep 11, 2017

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91222). This variant is also known as 811del4 and 808_811delCTGT. This premature translational stop signal has been observed in individual(s) with Lynch syndrome-related cancers (PMID: 7585065, 9718327, 15235034, 17312306, 27601186). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser271Argfs*2) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2024

The c.811_814delTCTG pathogenic mutation, located in coding exon 5 of the MSH2 gene, results from a deletion of 4 nucleotides between nucleotide positions 811 and 814, causing a translational frameshift with a predicted alternate stop codon (p.S271Rfs*2). This mutation has been detected in individuals meeting Amsterdam criteria and/or with Lynch syndrome tumors displaying microsatellite instability and loss of MSH2 protein expression (Liu B et al. Nat. Med. 1995 Apr;1(4):348-52; Roupret M et al. J. Med. Genet. 2004 Jul;41(7):e91; Lagerstedt Robinson et al. J. Natl. Cancer Inst. 2007 Feb;99(4):291-9; Ewald J et al. Br. J. Surg. 2007 Aug;94(8):1020-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 811del4, 808_811delCTGT, and 808delGTCT in published literature. In addition to the clinical data presented in the literature, 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. -

Endometrial carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH2 p.Ser271Argfs*2 variant was not identified in the literature nor was it identified in the dbSNP database. The variant was identified in ClinVar (classified as pathogenic by Invitae, Counyl, Ambry Genetics and two other submitters), and in UMD-LSDB (2x as causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.811_814del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 271 and leads to a premature stop codon at position 272. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in MSH2 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587779185; hg19: chr2-47641422;