ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3100C>T (p.Arg1034Trp)

gnomAD frequency: 0.00003  dbSNP: rs587779930
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000203004 SCV000257641 uncertain significance Lynch syndrome 2015-03-06 criteria provided, single submitter clinical testing
GeneDx RCV000219542 SCV000279304 uncertain significance not provided 2023-03-14 criteria provided, single submitter clinical testing Not observed at 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 cases and unaffected controls from a breast cancer study (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 25042771, 28912153, 17531815, 21120944, 33471991)
Counsyl RCV000410374 SCV000488920 uncertain significance Lynch syndrome 5 2016-07-18 criteria provided, single submitter clinical testing
Invitae RCV000524152 SCV000551047 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-10-04 criteria provided, single submitter clinical testing
Mendelics RCV000203004 SCV000837908 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000774606 SCV000908408 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-04 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 1034 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 5/278768 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.
Ambry Genetics RCV000774606 SCV001179911 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-17 criteria provided, single submitter clinical testing The p.R1034W variant (also known as c.3100C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 3100. The arginine at codon 1034 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sema4, Sema4 RCV000774606 SCV002535790 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-27 criteria provided, single submitter curation
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000410374 SCV003806857 uncertain significance Lynch syndrome 5 2022-10-06 criteria provided, single submitter clinical testing ACMG classification criteria: PM2 supporting, PP3 supporting
Myriad Genetics, Inc. RCV000410374 SCV004018924 uncertain significance Lynch syndrome 5 2023-03-28 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health RCV000203004 SCV004837113 uncertain significance Lynch syndrome 2023-08-15 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 1034 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/278768 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.

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