Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000168100 | SCV000218756 | benign | Hereditary nonpolyposis colorectal neoplasms | 2023-10-30 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000213342 | SCV000275221 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-17 | criteria provided, single submitter | clinical testing | The p.E1335D variant (also known as c.4005A>C), located in coding exon 10 of the MSH6 gene, results from an A to C substitution at nucleotide position 4005. The glutamic acid at codon 1335 is replaced by aspartic acid, an amino acid with highly similar properties. Another alteration at the same location, p.E1335A (c.4004A>C), has been reported in one family that met Amsterdam criteria and was shown to segregate with disease. The proband was diagnosed with colon cancer at age 42; however, tumor testing showed wild-type BRAF analysis, microsatellite stability, and normal IHC staining (Pérez-Cabornero L et al. J Mol Diagn. 2013 May;15(3):380-90). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Color Diagnostics, |
RCV000213342 | SCV000685483 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-21 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with aspartic acid at codon 1335 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 1/238052 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. |
Counsyl | RCV000663216 | SCV000786402 | uncertain significance | Lynch syndrome 5 | 2018-05-01 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001800508 | SCV002046627 | uncertain significance | not provided | 2021-02-02 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000213342 | SCV002536313 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-18 | criteria provided, single submitter | curation | |
Gene |
RCV001800508 | SCV002757704 | uncertain significance | not provided | 2022-11-21 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Absent from cases but observed in one control in a breast cancer case-control study (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 33471991, 17531815, 21120944, 12019211, 23523604, 29386642) |
Myriad Genetics, |
RCV000663216 | SCV004018872 | 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. |
Baylor Genetics | RCV003462256 | SCV004197590 | uncertain significance | Endometrial carcinoma | 2024-03-03 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003987391 | SCV004804233 | uncertain significance | not specified | 2024-01-08 | criteria provided, single submitter | clinical testing | Variant summary: MSH6 c.4005A>C (p.Glu1335Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 242940 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.4005A>C in individuals affected with Prostate Cancer and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 188188). Based on the evidence outlined above, the variant was classified as uncertain significance. |
All of Us Research Program, |
RCV003995607 | SCV004835196 | uncertain significance | Lynch syndrome | 2024-01-11 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with aspartic acid at codon 1335 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 1/238052 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. |