Submissions for variant NM_000179.3(MSH6):c.1255_1268del (p.Gln419fs)

dbSNP: rs876661251

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000217315	SCV000279899	pathogenic	not provided	2016-02-22	criteria provided, single submitter	clinical testing	This deletion of del14 nucleotides in MSH6 is denoted c.1255_1268del14 at the cDNA level and p.Gln419CysfsX11 (Q419CfsX11) at the protein level. The surrounding sequence is GTCT[del14]TGTC. The deletion causes a frameshift which changes a Glutamine to a Cysteine at codon 419, and creates a premature stop codon at position 11 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. Based on the currently available information, we consider this deletion to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586672	SCV000695778	likely pathogenic	Lynch syndrome	2016-05-24	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.1255_1268delCAGAACTTTGATCT (p.Gln419Cysfs) frameshift variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 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 (p.Arg482X, p.Lys545fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121340 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as Probaly Disease Variant.
Ambry Genetics	RCV002417978	SCV002678663	pathogenic	Hereditary cancer-predisposing syndrome	2019-02-21	criteria provided, single submitter	clinical testing	The c.1255_1268del14 pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of 14 nucleotides at nucleotide positions 1255 to 1268, causing a translational frameshift with a predicted alternate stop codon (p.Q419Cfs*11). 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.
Myriad Genetics, Inc.	RCV003454680	SCV004187078	pathogenic	Lynch syndrome 5	2023-08-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.