Submissions for variant NM_000179.2(MSH6):c.3957del (p.Ala1320fs) (rs587779297)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491256	SCV000580165	pathogenic	Hereditary cancer-predisposing syndrome	2016-12-12	criteria provided, single submitter	clinical testing	Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae	RCV000704103	SCV000833037	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2018-03-04	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the MSH6 gene (p.Ala1320Glnfs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acids of the MSH6 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 428325). A different truncation downstream of this variant (p.Leu1330Valfs*12), is a known Lynch syndrome founder mutation in the Ashkenazi Jewish population (PMID: 19851887, 21155762). This variant has been shown to abolish MSH6 expression and cause tumor microsatellite instability (PMID: 19851887). It has also been reported in individuals affected with constitutional mismatch repair deficiency syndrome (PMID: 24440087), and segregated with disease in a family affected with colorectal cancer (PMID: 14520694). This suggests that deletion of this region of the MSH6 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001008185	SCV001167951	pathogenic	not provided	2018-10-14	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in MSH6 is denoted c.3957delA at the cDNA level and p.Ala1320GlnfsX7 (A1320QfsX7) at the protein level. The normal sequence, with the base that is deleted in brackets, is GAAA[delA]GCAA. The deletion causes a frameshift which changes an Alanine to a Glutamine at codon 1320, and creates a premature stop codon at position 7 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature as a germline variant, it is predicted to cause loss of normal protein function through protein truncation. Even though nonsense-mediated decay is not expected to occur, due to the position of the variant, it is significant as the last 41 amino acids are lost and replaced with 6 incorrect amino acids. The disrupted region at the end of the gene is located within the binding site of MSH2 in the ATPase domain (Kariola 2002, Warren 2007, Kansikas 2011). Based on currently available evidence, we consider this deletion to be pathogenic.