Submissions for variant NM_000179.3(MSH6):c.3070C>T (p.Arg1024Trp)

dbSNP: rs370505117

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000227649	SCV000283779	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491202	SCV000580331	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	The p.R1024W variant (also known as c.3070C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 3070. The arginine at codon 1024 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was also detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000491202	SCV000685348	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1024 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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 1/242432 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	RCV000985838	SCV001134419	uncertain significance	not provided	2019-05-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000985838	SCV001804490	uncertain significance	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with breast and ovarian cancer (Tung 2015); This variant is associated with the following publications: (PMID: 23621914, doi:10.5923/j.bioinformatics.20160602.03, 25186627, 17531815, 21120944)
Sema4, Sema4	RCV000491202	SCV002535789	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002494619	SCV002775449	uncertain significance	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2021-08-31	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000491202	SCV004014972	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998725	SCV004834578	uncertain significance	Lynch syndrome	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1024 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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 1/242432 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.