Submissions for variant NM_000179.3(MSH6):c.652A>T (p.Lys218Ter)

dbSNP: rs587779315

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075019	SCV000108240	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV001386352	SCV001586543	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-06-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89550). This premature translational stop signal has been observed in individual(s) with clinical features of MSH6-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys218*) 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).
Ambry Genetics	RCV002362702	SCV002660556	pathogenic	Hereditary cancer-predisposing syndrome	2019-10-24	criteria provided, single submitter	clinical testing	The p.K218* pathogenic mutation (also known as c.652A>T), located in coding exon 4 of the MSH6 gene, results from an A to T substitution at nucleotide position 652. This changes the amino acid from a lysine to a stop codon within coding exon 4. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355616	SCV001550549	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Lys218* variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs587779315) as "with Pathogenic allele", in ClinVar (1x as Pathogenic by InSiGHT) and in the Insight Colon Cancer Gene Variant Database (as class 5: pathogenic). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.652A>T variant leads to a premature stop codon at position 218 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome related cancers and this is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.