Submissions for variant NM_000179.2(MSH6):c.3379_3438+5del (rs1553331676)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074844	SCV000108056	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon (also interrupts canonical donor splice site)
GeneDx	RCV000214789	SCV000279555	pathogenic	not provided	2015-11-11	criteria provided, single submitter	clinical testing	This deletion of 65 nucleotides in MSH6 is denoted c.3379_3438+5del65 at the cDNA level and p.Ala1127LeufsX15 (A1127LfsX15) at the protein level. The surrounding sequence is CAAA[del65]tgat, where the capital letters are exonic and lowercase are intronic. The deletion causes a frameshift, which changes an Alanine to a Leucine at codon 1127, and creates a premature stop codon at position 15 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation and to destroy a canonical splice donor site resulting in abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. MSH6 c.3379_3438+5del65 has been reported in at least one individual with early onset colon cancer and a family history consistent with Lynch syndrome and the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Steinke 2008, Thompson 2014). We consider this variant to be pathogenic.
Ambry Genetics	RCV000490849	SCV000580107	pathogenic	Hereditary cancer-predisposing syndrome	2017-10-26	criteria provided, single submitter	clinical testing	Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae	RCV001038331	SCV001201797	likely pathogenic	Hereditary nonpolyposis colon cancer	2019-11-27	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon(s) 5 (c.3379_3438+5del) of the MSH6 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18301448, Invitae). ClinVar contains an entry for this variant (Variation ID: 89377). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color	RCV000490849	SCV001350203	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-06-26	criteria provided, single submitter	clinical testing