Submissions for variant NM_000179.3(MSH6):c.3920_3923dup (p.Pro1309fs)

dbSNP: rs1572747278

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825600	SCV000966943	likely pathogenic	Lynch syndrome	2017-12-14	criteria provided, single submitter	clinical testing	The p.Pro1309fs variant in MSH6 has been reported in 2 individual with MSH6-asso ciated cancers (Haraldsdottir 2016, Hampel 2008) and was absent from large popul ation studies, though the ability of these studies to accurately detect indels m ay be limited. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1309 and leads to a prematu re termination codon 11 amino acids downstream. This termination codon occurs wi thin the terminal 50 bases of the second to last exon and is more likely to esca pe nonsense mediated decay (NMD), resulting in a truncated protein. Truncating v ariants downstream of this variant have been reported in individuals with Lynch syndrome. In summary, although additional studies are required to fully establis h its clinical significance, the p.Pro1309fs variant is likely pathogenic. ACMG/ AMP Criteria applied: PVS1_Strong; PM2; PS4_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358735	SCV001554582	likely pathogenic	Hereditary nonpolyposis colon cancer	2021-03-19	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3920_3923dupATCT (p.Pro1309SerfsX11) 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 was absent in 250380 control chromosomes (gnomAD). c.3920_3923dupATCT has been reported in the literature in individuals affected with Lynch Syndrome or colorectal cancer (Hampel_2008, Haraldsdottir_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001388972	SCV001590166	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-11-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Arg1334Hisfs*14) have been determined to be pathogenic (PMID: 24323032; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 667011). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18809606, 26866578). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro1309Serfs*11) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acid(s) of the MSH6 protein.
Myriad Genetics, Inc.	RCV003453748	SCV004185751	pathogenic	Lynch syndrome 5	2023-08-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.