Submissions for variant NM_000179.3(MSH6):c.3848_3850dup (p.Ile1283dup)

dbSNP: rs1553333420

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000461225	SCV000551297	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing	This variant, c.3848_3850dup, results in the insertion of 1 amino acid(s) of the MSH6 protein (p.Ile1283dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760500213, gnomAD 0.006%). This variant has been observed in individual(s) with Lynch syndrome (PMID: 24689082, 27601186). ClinVar contains an entry for this variant (Variation ID: 410530). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000485186	SCV000569625	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing	In-frame duplication of 1 amino acid in a non-repeat region; Observed in at least two individuals suspected of having Lynch syndrome, and was identified at similar frequencies between Icelandic colorectal cancer patients and controls (p=0.69) (Lagerstedt-Robinson et al., 2016; Haraldsdottir et al., 2017); This variant is associated with the following publications: (PMID: 24689082, 28466842, 17531815, 21120944, 27601186)
Ambry Genetics	RCV000574392	SCV000662367	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-02	criteria provided, single submitter	clinical testing	The c.3848_3850dupTTA variant (also known as p.I1283dup), located in coding exon 9 of the MSH6 gene, results from an in-frame duplication of TTA at nucleotide positions 3848 to 3850. This results in the duplication of an extra isoleucine residue at codon 1283. This alteration has been reported in multiple individuals with personal and/or family history consistent with Lynch syndrome (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835; Haraldsdottir S et al. Nat Commun, 2017 05;8:14755). However, this variant has been identified in multiple probands whose Lynch syndrome-associated tumors demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC) (Ambry internal data; Haraldsdottir S et al. Nat Commun, 2017 05;8:14755). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000574392	SCV000685454	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This variant causes an in-frame duplication of one amino acid of the MSH6 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated disease or suspected of Lynch syndrome (PMID: 24689082, 27601186, 28466842). However, several individuals affected with colorectal cancer had tumors that displayed intact protein via immunohistochemistry analysis and the variant has also been identified in healthy controls, with no significant association with colorectal cancer found in the study population (PMID: 28466842). This variant has been identified in 7/282272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731697	SCV001983422	uncertain significance	not specified	2021-09-14	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3848_3850dupTTA (p.Ile1283dup) results in an in-frame duplication with the insertion of one amino acid into the C-terminal domain of the MSH6 protein (IPR000432). The variant allele was found at a frequency of 2.5e-05 in 282272 control chromosomes, predominantly found in the European subpopulation with an allele frequency of 5.4e-05 in the gnomAD database. However, the variant was found at an even higher frequency in the Swedish (5/26108 alleles; allele frequency of ~0.0002); and this frequency is higher than the maximum expected for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), suggesting a benign role for the variant. The variant, c.3848_3850dupTTA, has been reported in the literature in Scandinavian individuals affected with colon cancer and suspected Lynch syndrome (Hansen_2014, Lagerstedt-Robinson_2016, Haraldsdottir_2017), but was also reported to be found with similar allele frequencies among healthy Icelandic controls (Haraldsdottir_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001731697	SCV002552368	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001859	SCV004835152	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This variant causes an in-frame duplication of one amino acid of the MSH6 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated disease or suspected of Lynch syndrome (PMID: 24689082, 27601186, 28466842). However, several individuals affected with colorectal cancer had tumors that displayed intact protein via immunohistochemistry analysis and the variant has also been identified in healthy controls, with no significant association with colorectal cancer found in the study population (PMID: 28466842). This variant has been identified in 7/282272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GenomeConnect - Invitae Patient Insights Network	RCV003483628	SCV004228555	not provided	Lynch syndrome 5		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 05-02-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.