Submissions for variant NM_000179.3(MSH6):c.1918GAA[1] (p.Glu641del)

dbSNP: rs786203970

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167505	SCV000218363	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-22	criteria provided, single submitter	clinical testing	The c.1921_1923delGAA variant (also known as p.E641del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame GAA deletion at nucleotide positions 1921 to 1923. This results in the in-frame deletion of a glutamic acid at codon 641. This variant was reported in one Puerto Rican patient with breast cancer who previously tested negative for BRCA1/2 mutations (Dutil J et al. Sci Rep, 2019 11;9:17769). The deleted amino acid position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000629967	SCV000750923	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing	This variant, c.1921_1923del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Glu641del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762299881, gnomAD 0.003%). This variant has been observed in individual(s) with breast cancer (PMID: 31780696). ClinVar contains an entry for this variant (Variation ID: 187749). 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	RCV000167505	SCV000911467	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 31780696). This variant has been identified in 1/245838 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	RCV001800507	SCV002047309	uncertain significance	not provided	2021-03-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001800507	SCV002526277	uncertain significance	not provided	2022-06-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Identified in a patient with breast cancer (Dutil 2019); This variant is associated with the following publications: (PMID: 31780696, 17531815, 21120944)
All of Us Research Program, National Institutes of Health	RCV003995596	SCV004835589	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 31780696). This variant has been identified in 1/245838 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.