ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.4004A>C (p.Glu1335Ala) (rs564434147)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129804 SCV000184615 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-13 criteria provided, single submitter clinical testing The p.E1335A variant (also known as c.4004A>C), located in coding exon 10 of the MSH6 gene, results from an A to C substitution at nucleotide position 4004. The glutamic acid at codon 1335 is replaced by alanine, an amino acid with dissimilar properties. This variant was reported in one family that met Amsterdam criteria and segregated 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 alteration has also been reported as a variant of unknown significance, detected in a low-grade malignant astrocytoma that showed microsatellite stability and loss of staining for MLH1, MSH2, and MSH6 on IHC (Rodríguez-Hernández I et al. PLoS One. 2013 Sep 20;8(9):e76401). 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 for this variant is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000204360 SCV000261608 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 1335 of the MSH6 protein (p.Glu1335Ala). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs564434147, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with Lynch syndrome and astrocytoma (PMID: 23523604, 24073290). ClinVar contains an entry for this variant (Variation ID: 141327). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000656905 SCV000339599 uncertain significance not provided 2016-02-04 criteria provided, single submitter clinical testing
Counsyl RCV000409369 SCV000489131 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-25 criteria provided, single submitter clinical testing
GeneDx RCV000656905 SCV000565241 likely benign not provided 2019-12-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23523604, 28528518, 24073290)
Color Health, Inc RCV000129804 SCV000685482 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-22 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with alanine 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 performed for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 23523604), astrocytoma (PMID: 24073290), and breast and/or ovarian cancer (PMID: 28528518). This variant has also been identified in 18/237668 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.
Mendelics RCV000708898 SCV000837935 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000409369 SCV001135869 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001375525 SCV001572381 likely benign not specified 2021-04-01 criteria provided, single submitter clinical testing Variant summary: MSH6 c.4004A>C (p.Glu1335Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.7e-05 in 242576 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (8.7e-05 vs 0.00014), allowing no conclusion about variant significance. c.4004A>C has been reported in the literature in individuals undergoing multigene panel testing for hereditary cancers such as Lynch, low grade astrocytoma and breast (example, Perez-Cabornero_2013, Rodriguez-Hernandez_2013, Cock-Rada_2017, Nikitin_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the literature and observed at our laboratory (BRCA1 c.5266dupC, p.Gln1756Profs, Nikitin_2020; PALB2 c.1317delG, p.Phe440fs, internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A study that computed a tumor characteristic likelihood ratio (TCLR) in combination with in-silico predictors and multifactorial variant prediction (MVP) model including allele frequency, co-occurrence, co-segregation, clinical and family history information classified this variant a "likely benign". Eight 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. Some submitters cite overlapping but not all evidences utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000656905 SCV001551880 uncertain significance not provided no assertion criteria provided clinical testing The MSH6 p.Glu1335Ala variant was identified in 3 of 680 proband chromosomes (frequency: 0.004) from individuals or families with Lynch syndrome, astrocytoma, and breast or ovarian cancer and was not identified in 694 control chromosomes from healthy individuals (Perez-Cabornero 2013, Rodriguez-Hernandez 2013, Cock-Rada 2018). The variant was also identified in dbSNP (ID: rs564434147 as "With Uncertain significance allele"), ClinVar (6x as uncertain significance by Ambry Genetics, Invitae, Counsyl, GeneDx, Color Genomics, and EGL Genetic), and UMD-LSDB (1x as unclassified variant). The variant was not identified in the COGR, Cosmic, MutDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in control databases in 18 of 237668 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 7 of 32242 chromosomes (freq: 0.0002), European Non-Finnish in 2 of 108812 chromosomes (freq: 0.00008), and South Asian in 9 of 28764 chromosomes (freq: 0.0003); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Glu1335 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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