Submissions for variant NM_000179.3(MSH6):c.3759AGA[3] (p.Glu1254dup)

gnomAD frequency: 0.00002  dbSNP: rs587779937

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218234	SCV000278634	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-16	criteria provided, single submitter	clinical testing	The c.3762_3764dupAGA variant (also known as p.E1254dup), located in coding exon 8 of the MSH6 gene, results from an in-frame duplication of AGA at nucleotide positions 3762 to 3764. This results in the duplication of an extra residue between codons 1254 and 1255. Based on internal structural analysis p.E1254dup is not tolerated. This amino acid position is well 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). Based on the available evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590359	SCV000695886	uncertain significance	not provided	2015-12-07	criteria provided, single submitter	clinical testing
Invitae	RCV001068250	SCV001233349	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-03-19	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 234123). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (rs779334383, gnomAD 0.0009%). This variant, c.3762_3764dup, results in the insertion of 1 amino acid(s) of the MSH6 protein (p.Glu1254dup), but otherwise preserves the integrity of the reading frame.
Baylor Genetics	RCV003463599	SCV004195757	uncertain significance	Endometrial carcinoma	2023-05-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998598	SCV004835131	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This variant causes an in-frame duplication of one amino acid of 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 1/251190 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356797	SCV001552062	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Glu1254dup variant was not identified in the literature nor was it identified in the UMD-LSDB, database. The variant was identified in dbSNP (ID: rs876660864) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Ambry Genetics and Integrated Genetics/Laboratory Corporation of America). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame duplication resulting in the duplication of a Glutamic acid (Glu) residue at codon 1254; the impact of this alteration on MSH6 protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.