Submissions for variant NM_000251.3(MSH2):c.1838dup (p.Asn613fs)

dbSNP: rs1114167815

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491996	SCV000580453	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-14	criteria provided, single submitter	clinical testing	The c.1838dupA pathogenic mutation, located in coding exon 12 of the MSH2 gene, results from a duplication of A at nucleotide position 1838, causing a translational frameshift with a predicted alternate stop codon (p.N613Kfs*31). This pathogenic mutation has been reported in one HNPCC family that had a strong history of ureter, bladder, and kidney cancers (Geary J et al. Fam Cancer. 2008;7(2):163-72). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781568	SCV000919720	likely pathogenic	Lynch syndrome	2018-11-14	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1838dupA (p.Asn613LysfsX31) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. p.Arg621X, p.Arg680X, p.Gln681X). The variant was absent in 246258 control chromosomes (gnomAD). The variant, c.1838dupA, has been reported in the literature in a family affected with Lynch Syndrome (Geary 2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001380770	SCV001578928	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-02-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn613Lysfs*31) 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: 17939062). ClinVar contains an entry for this variant (Variation ID: 428465). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003449343	SCV004188122	pathogenic	Lynch syndrome 1	2023-08-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.