Submissions for variant NM_000179.3(MSH6):c.3936_3951del (p.Ile1313fs)

dbSNP: rs1553333635

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589697	SCV000695897	likely pathogenic	Hereditary nonpolyposis colon cancer	2019-04-18	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3936_3951del16 (p.Ile1313GlufsX9) 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 (eg. e.g., c.3959_3962delCAAG [p.Ala1320fsX6], c.3984_3987dupGTCA [p.Leu1330fsX12], and c.3991C>T [p.Arg1331X]). The variant was absent in 250130 control chromosomes. c.3936_3951del16 has been reported in the literature in an individual affected with Adenocortical carcinoma (ACC) where it was noted that the identification of germline MSH6 mutations support recent observations that ACC is a Lynch-syndrome associated cancer (Zheng_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001040765	SCV001204354	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-03-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile1313Glufs*9) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the MSH6 protein. This variant is not present in population databases (gnomAD no frequency). 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: 495718). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 14520694, 19851887, 21155762). 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.
Myriad Genetics, Inc.	RCV003451327	SCV004185983	pathogenic	Lynch syndrome 5	2023-10-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.