Submissions for variant NM_000179.3(MSH6):c.3762_3763delinsTT (p.Glu1254_Asp1255delinsAspTyr)

dbSNP: rs878853738

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232565	SCV000283821	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-09-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000478739	SCV000565235	uncertain significance	not provided	2018-10-02	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3762_3763delAGinsTT at the cDNA level and p.Glu1254_Asp1255delinsAspTyr (E1254_D1255delinsDY) at the protein level. The surrounding sequence is TAGA[delAG][insTT]ATTA. The deletion and insertion results in the replacement of a Glutamic Acid and an Aspartic Acid residue with an Aspartic Acid and a Tyrosine residue, creating two adjacent missense changes: Glu1254Asp and Asp1255Tyr. This combined variant has not, to our knowledge, been reported in the literature as a pathogenic or benign germline variant. MSH6 c.3762_3763delAGinsTT was not observed in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 c.3762_3763delAGinsTT is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000564937	SCV000669967	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-25	criteria provided, single submitter	clinical testing	The c.3762_3763delAGinsTT variant (also known as p.E1254_D1255delinsDY), located in coding exon 8 of the MSH6 gene, results from an in-frame deletion of AG and insertion of TT at nucleotide positions 3762 and 3763. This results in the substitution of glutamate and aspartate residues for aspartate and tyrosine residues at codon 1254 and 1255. This amino acid region 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 variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000564937	SCV001735063	uncertain significance	Hereditary cancer-predisposing syndrome	2020-05-26	criteria provided, single submitter	clinical testing	This variant replaces glutamic acid with aspartic acid at codon 1254 and aspartic acid with tyrosine at codon 1255 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 hereditary cancer 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.
Genetic Services Laboratory, University of Chicago	RCV001818564	SCV002068637	uncertain significance	not specified	2019-02-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818564	SCV002765959	uncertain significance	not specified	2022-11-17	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3762_3763delinsTT (p.Glu1254_Asp1255delinsAspTyr) results in an in-frame deletion-insertion that is predicted to delete/insert 2 amino acids from the protein and also cause changes in 2 amino acids within the DNA mismatch repair protein MutS, C-terminal domain (IPR000432). The variant was absent in 251194 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3762_3763delinsTT in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five 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.