Submissions for variant NM_000251.3(MSH2):c.2135dup (p.Gly713fs)

dbSNP: rs63751453

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076406	SCV000107435	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Invitae	RCV000706282	SCV000835322	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly713Argfs*4) 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 Lynch syndrome or colorectal cancer (PMID: 15713769, 19698169). This variant is also known as c.2135_2136insT, V712Xfs, and Val712ValfsX4. ClinVar contains an entry for this variant (Variation ID: 90904). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003452892	SCV004187992	pathogenic	Lynch syndrome 1	2023-08-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Color Diagnostics, LLC DBA Color Health	RCV003584544	SCV004356724	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-26	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 13 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: 15713769, 21311894) and families with suspected Lynch syndrome (PMID: 21642682). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353601	SCV000592537	pathogenic	not provided		no assertion criteria provided	clinical testing	The p.Gly713ArgfsX4 variant is reported in the literature in 4 of 1314 proband chromosomes (frequency of 0.003) meeting Amsterdam and Bethesda criteria of HNPCC; although no control chromosomes were tested to establish the variants frequency in the general population (Casey 2005, Moussa 2011, Bonadona 2011). It is listed in dbSNP database as coming from a "clinical source" (ID#: rs63751453) but no frequency information was provided therefore not very informative for assessing the population frequency. Mutations causing frameshift and truncation of the MSH2 protein have been shown to be clinically important, and loss of function of the MSH2 gene represents an established disease mechanism in HNPPC patients. This variant (listed as 2135_2136insT) has shown to lead exon 13 skipping and reduced mRNA expression (<90%) of the affected allele, as well as loss of MSH2 protein by immunohistochemistry analysis (Casey 2005). Based on the above information, this variant is classified as Pathogenic.