Submissions for variant NM_000179.3(MSH6):c.3729ATT[1] (p.Leu1244del)

dbSNP: rs876658650

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219285	SCV000275689	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-29	criteria provided, single submitter	clinical testing	The c.3732_3734delATT variant (also known as p.L1244del) is located in coding exon 8 of the MSH6 gene. This variant results from an in-frame ATT deletion between nucleotide positions 3732 and 3734 and a deletion of the leucine at codon 1244. This alteration has been identified in multiple families who meet Amsterdam Criteria for Lynch Syndrome and it segregates with disease in these families (Ambry internal data). Based on internal structural assessment, this alteration disrupts the structure of the ATPase domain (Warren JJ et al. Mol. Cell. 2007 May;26:579-92; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000629717	SCV000750673	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-30	criteria provided, single submitter	clinical testing	This variant, c.3732_3734del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Leu1244del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Lynch syndrome-related cancers (Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 231746). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193097	SCV001361705	uncertain significance	not specified	2019-09-17	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3732_3734delATT (p.Leu1244del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 251206 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3732_3734delATT in individuals affected with Hereditary Non-Polyposis Colon Cancer 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 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001565850	SCV001789279	likely pathogenic	not provided	2023-03-07	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 1 amino acid in a non-repeat region; Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17531815, 21120944)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001565850	SCV002049146	uncertain significance	not provided	2020-11-17	criteria provided, single submitter	clinical testing	The MSH6 c.3732_3734delATT; p.Leu1244del variant (rs876658650), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 231746). However, a nearby in-frame deletion, p.Arg1242del has been reported in individuals with colon cancer and has been classified likely pathogenic by the InSIGHT expert panel (Thompson 2014). The c.3732_3734delATT variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes a single leucine residue leaving the rest of the protein in-frame. Due to limited information, the clinical significance of the c.3732_3734delATT; p.Leu1244de variant is uncertain at this time.
Color Diagnostics, LLC DBA Color Health	RCV000219285	SCV004357750	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid located in the ATPase domain of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Lynch syndrome (ClinVar SCV000750673.6, SCV000275689.6). It has been shown that this variant segregates with disease (communication with an external laboratory; ClinVar SCV000275689.6). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV003997923	SCV004830336	likely pathogenic	Lynch syndrome	2023-06-20	criteria provided, single submitter	clinical testing	This variant has been reported in multiple individuals with Lynch Syndrome (Ambry, Invitae internal data listed in ClinVar). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described. (PMID: 17531815) This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant has been reported to co-segregate with disease in more than one family (Ambry, Invitae internal data).