Submissions for variant NM_000179.3(MSH6):c.166_171dup (p.54GP[3])

gnomAD frequency: 0.00002  dbSNP: rs786201776

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164241	SCV000214864	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	The c.166_171dupGGGCCC variant (also known as p.G56_P57dup), located in coding exon 1 of the MSH6 gene, results from an in-frame duplication of GGGCCC at nucleotide positions 166 to 171. This results in the duplication of 2 extra residues (GP) between codons 56 and 57. This amino acid region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral 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.
GeneDx	RCV000486035	SCV000567610	uncertain significance	not provided	2016-04-29	criteria provided, single submitter	clinical testing	This duplication of six nucleotides is denoted MSH6 c.166_171dupGGGCCC at the cDNA level and p.Gly56_Pro57dup (G56_P57dup) at the protein level. The normal sequence, with the bases that are duplicated in braces, is GCCT[GGGCCC]AGGC. This in-frame duplication occurs in a region which is not conserved and is not located in a known functional domain (Terui 2013, Kariola 2002). This variant has not, to our knowledge, been published in the literature as either pathogenic or benign. Since in frame duplications may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH6 Gly56_Pro57dup to be a variant of uncertain significance.
Invitae	RCV000547641	SCV000624676	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This variant, c.166_171dup, results in the insertion of 2 amino acid(s) of the MSH6 protein (p.Gly56_Pro57dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs786201776, gnomAD 0.004%). 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: 184901). 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.
Color Diagnostics, LLC DBA Color Health	RCV000164241	SCV000908337	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-24	criteria provided, single submitter	clinical testing	This variant causes an in-frame duplication of two amino acids 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/201112 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267908	SCV002552270	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462128	SCV004197723	uncertain significance	Endometrial carcinoma	2023-09-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000486035	SCV004224908	uncertain significance	not provided	2022-03-16	criteria provided, single submitter	clinical testing	PM2, PM4
All of Us Research Program, National Institutes of Health	RCV003995329	SCV004828119	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This variant causes an in-frame duplication of two amino acids 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/201112 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.