Submissions for variant NM_000179.3(MSH6):c.159TGGGCC[3] (p.54GP[3])

dbSNP: rs767894453

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484193	SCV000565208	uncertain significance	not provided	2017-02-13	criteria provided, single submitter	clinical testing	This in-frame duplication of six nucleotides in MSH6 is denoted c.165_170dupTGGGCC at the cDNA level and p.Gly56_Pro57dup (G56_P57dup) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is GGCC[dupTGGGCC]CAGG. This duplication occurs in a region that is not conserved and is not located in a known functional domain (Kariola 2002, Kansikas 2010). This variant has not, to our knowledge, been published in the literature as 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	RCV000535191	SCV000624675	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-06-20	criteria provided, single submitter	clinical testing	This variant, c.165_170dup, 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 (rs767894453, gnomAD 0.01%). 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: 418318). 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.
Ambry Genetics	RCV001012572	SCV001173041	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-09	criteria provided, single submitter	clinical testing	The c.165_170dupTGGGCC variant (also known as p.G56_P57dup), located in coding exon 1 of the MSH6 gene, results from an in-frame duplication of TGGGCC at nucleotide positions 165 to 170. This results in the duplication of 2 extra residues (GP) between codons 56 and 57. These amino acid positions are 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.
Color Diagnostics, LLC DBA Color Health	RCV001012572	SCV001353862	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This variant causes the duplication of six nucleotides in exon 1 of the MSH6 gene, resulting in an in-frame insertion of two amino acids in the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/183106 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484193	SCV004221151	uncertain significance	not provided	2022-09-29	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0000055 (1/183106 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV004002245	SCV004828097	uncertain significance	Lynch syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This variant causes the duplication of six nucleotides in exon 1 of the MSH6 gene, resulting in an in-frame insertion of two amino acids in the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/183106 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.