Submissions for variant NM_000251.3(MSH2):c.204del (p.Pro69fs)

dbSNP: rs63750199

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076373	SCV000107400	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000491774	SCV000580610	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-12	criteria provided, single submitter	clinical testing	The c.204delG pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 204, causing a translational frameshift with a predicted alternate stop codon (p.P69Rfs*15). This alteration has been seen in multiple unrelated families with Lynch syndrome (Lagerstedt et al J. Natl. Cancer Inst. 2007 Feb;99(4):291-9; Goldberg Y et al Clin. Genet. 2015 Jun;87(6):549-53; Wahlberg SS et al Int. J. Cancer 1997 Feb;74(1):134-7; Liu T et al Genes Chromosomes Cancer 2000;27 (1) :17-25). Of note, this alteration is also designated as 201delG in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV000657242	SCV000778971	pathogenic	not provided	2017-11-22	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in MSH2 is denoted c.204delG at the cDNA level and p.Pro69ArgfsX15 (P69RfsX15) at the protein level. The normal sequence, with the base that is deleted in brackets, is TGGG[delG]CCGG. The deletion causes a frameshift which changes a Proline to an Arginine at codon 69, and creates a premature stop codon at position 15 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.204delG reportedly segregated with disease in a family fulfilling Amsterdam criteria, with a history of colorectal and endometrial cancer (Wahlberg 1997). We consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001210613	SCV001382109	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro69Argfs*15) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 9036882, 25430799). This variant is also known as c.201delG. ClinVar contains an entry for this variant (Variation ID: 90871). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262885	SCV001440921	pathogenic	Breast carcinoma	2019-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003452884	SCV004188149	pathogenic	Lynch syndrome 1	2023-07-26	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
All of Us Research Program, National Institutes of Health	RCV000076373	SCV004830196	pathogenic	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 1 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 affected with Lynch syndrome (PMID: 9036882, 17312306, 25430799, 27601186). 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.