Submissions for variant NM_000179.3(MSH6):c.3922_3940dup (p.Gln1314fs)

dbSNP: rs1553333598

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197204	SCV001367841	pathogenic	Endometrial carcinoma	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4,PP5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527181	SCV003213297	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-06-21	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 30608896). ClinVar contains an entry for this variant (Variation ID: 433928). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Arg1334Serfs*7) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1314Profs*11) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the MSH6 protein.
Myriad Genetics, Inc.	RCV003449412	SCV004187306	pathogenic	Lynch syndrome 5	2023-08-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV001197204	SCV004195829	pathogenic	Endometrial carcinoma	2023-03-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000501467	SCV000592660	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Gln1314ProfsX11 variant was not identified in the literature, nor was it identified in dbSNP, HGMD, UMD, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, “MMR Gene Unclassified Variants Database”, or COSMIC database. The p.Gln1314ProfsX11 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1314 and leads to a premature stop codon 11 codons downstream. This alteration is then predicted to result in 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 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.