Submissions for variant NM_000179.3(MSH6):c.1590del (p.Ser532fs)

dbSNP: rs587779216

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074667	SCV000107869	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000491242	SCV000580102	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	The c.1590delT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 1590, causing a translational frameshift with a predicted alternate stop codon (p.S532Lfs*39). 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.
Invitae	RCV001070809	SCV001236081	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser532Leufs*39) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with MSH6-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89204). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811350	SCV001473597	pathogenic	not provided	2019-10-22	criteria provided, single submitter	clinical testing	The MSH6 c.1590delT; p.Ser532fs variant (rs587779216), to our knowledge, is not reported in the medical literature but is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 89204). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Several frameshift variants downstream the c.1590delT variant have been reported and are considered to be pathogenic (Lagerstedt-Robinson 2016). Based on available information, the c.1590delT variant is considered to be pathogenic. REFERENCES Lagerstedt-Robinson K et al. Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. Oncol Rep. 2016 Nov;36(5):2823-2835.
Myriad Genetics, Inc.	RCV003450927	SCV004187321	pathogenic	Lynch syndrome 5	2023-08-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.