Submissions for variant NM_000251.3(MSH2):c.11dup (p.Pro5fs)

dbSNP: rs730881775

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160630	SCV000211229	pathogenic	not provided	2023-01-25	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in an individual with colon cancer (Susswein et al., 2016); This variant is associated with the following publications: (PMID: 26681312)
Ambry Genetics	RCV000491987	SCV000580496	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-23	criteria provided, single submitter	clinical testing	The c.11dupA pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a duplication of A at nucleotide position 11, causing a translational frameshift with a predicted alternate stop codon (p.P5Afs*77). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160630	SCV001134328	pathogenic	not provided	2018-11-02	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204547	SCV001375758	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-04-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro5Alafs*77) 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 (PMID: 26681312; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182592). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003453271	SCV004186835	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.