Submissions for variant NM_000179.3(MSH6):c.172_177dup (p.Arg58_Pro59dup)

dbSNP: rs876661161

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213272	SCV000279689	uncertain significance	not provided	2015-12-15	criteria provided, single submitter	clinical testing	This in-frame duplication of 6 nucleotides in MSH6 is denoted c.172_177dupAGGCCC at the cDNA level and p.Arg58_Pro59dup (R58_P59dup) at the protein level. The normal sequence, with the bases that are duplicated in braces, is AGGCCC{AGGCCC}TTGG. This duplication occurs in a region which is not conserved and is not located in a known functional domain (Terui 2013). 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 Arg58_Pro59dup to be a variant of uncertain significance.
Ambry Genetics	RCV000572726	SCV000670020	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-04	criteria provided, single submitter	clinical testing	The c.172_177dupAGGCCC variant (also known as p.R58_P59dup), located in coding exon 1 of the MSH6 gene, results from an in-frame duplication of AGGCCC at nucleotide positions 172 to 177. This results in the duplication of 2 extra residues (RP) between codons 58 and 59. In a study of 63 cases of non-medullary thyroid cancer, this duplication (designated G56GPR) was identified in one proband with sporadic papillary thyroid cancer who also carried the MSH6 variant p.A53D. Both alterations were deemed likely benign, based on in silico predictions (Yu Y et al. Sci Rep, 2015 Nov;5:16129). The duplicated nucleotide region is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000803974	SCV000943863	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-04	criteria provided, single submitter	clinical testing	This variant, c.172_177dup, results in the insertion of 2 amino acid(s) of the MSH6 protein (p.Arg58_Pro59dup), 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 individual(s) with pancreatic cancer (PMID: 35171259). This variant is also known as c.177_178insAGGCCC. ClinVar contains an entry for this variant (Variation ID: 234685). 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.
Baylor Genetics	RCV003469110	SCV004197592	uncertain significance	Endometrial carcinoma	2023-10-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000572726	SCV004356774	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	This variant causes an in-frame duplication 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 not been identified 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.
All of Us Research Program, National Institutes of Health	RCV003998639	SCV004830381	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This variant causes an in-frame duplication 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 not been identified 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.