Submissions for variant NM_000179.3(MSH6):c.2269_2270del (p.Thr757fs)

dbSNP: rs876661025

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000216101	SCV000279250	pathogenic	not provided	2016-01-21	criteria provided, single submitter	clinical testing	This deletion of 2 nucleotides in MSH6 is denoted c.2269_2270delAC at the cDNA level and p.Thr757ProfsX6 (T757PfsX6) at the protein level. The normal sequence, with the bases that are deleted in brace, is AGGA[AC]CCTA. The deletion causes a frameshift, which changes a Threonine to a Proline at codon 757, and creates a premature stop codon at position 6 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. we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688578	SCV000816197	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr757Profs*6) 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). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 234448). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271474	SCV002556192	likely pathogenic	Hereditary nonpolyposis colon cancer	2022-06-27	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2269_2270delAC (p.Thr757ProfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 4e-06 in 251080 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2269_2270delAC in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002444869	SCV002737999	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-19	criteria provided, single submitter	clinical testing	The c.2269_2270delAC pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 2269 to 2270, causing a translational frameshift with a predicted alternate stop codon (p.T757Pfs*6). 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.	RCV003454664	SCV004188315	pathogenic	Lynch syndrome 5	2023-08-16	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	RCV003463609	SCV004197628	likely pathogenic	Endometrial carcinoma	2023-10-14	criteria provided, single submitter	clinical testing