Submissions for variant NM_000179.3(MSH6):c.1645del (p.Ser549fs)

dbSNP: rs876661033

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214419	SCV000279280	pathogenic	not provided	2015-11-24	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in MSH6 is denoted c.1645delT at the cDNA level and p.Ser549LeufsX22 (S549LfsX22) at the protein level. The normal sequence, with the base that is deleted in brackets, is AGAT[T]CTTC. The deletion causes a frameshift, which changes a Serine to a Leucine at codon 549, and creates a premature stop codon at position 22 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Invitae	RCV001243735	SCV001416916	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-10-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 234464). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser549Leufs*22) in the MSH6 gene. It is expected to result in an absent or disrupted protein product.
Ambry Genetics	RCV003298283	SCV003996569	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	The c.1645delT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 1645, causing a translational frameshift with a predicted alternate stop codon (p.S549Lfs*22). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003454665	SCV004185709	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.
GenomeConnect - Invitae Patient Insights Network	RCV001535644	SCV001749680	not provided	Lynch syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 05-29-2015 by GeneDx. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.