ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2555AGA[2] (p.Lys854del) (rs587782858)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132477 SCV000187571 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-26 criteria provided, single submitter clinical testing ​The c.2561_2563delAGA variant (also known as p.K854del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame AGA deletion at nucleotide positions 2561 to 2563, causing the removal of a highly-conserved lysine residue at codon 854. This alteration has been reported in a French patient with a clinical diagnosis of Constitutional Mismatch Repair Deficiency (CMMRD) syndrome in conjunction with a known MSH6 pathogenic mutation; however, authors note that the clinical presentation is more consistent with an early form of Lynch syndrome than with CMMRD, suggesting that this alteration may not be completely inactivating (Bougeard G et al. Fam. Cancer. 2014 Mar;13:131-5; Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8). This alteration has also been identified in several individuals with Lynch-associated tumors that were microsatellite stable (MSS) and/or had normal mismatch repair protein expression on immunohistochemistry (IHC) (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000226221 SCV000283756 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-27 criteria provided, single submitter clinical testing This variant, c.2561_2563delAGA, results in the deletion of 1 amino acid of the MSH6 protein (p.Lys854del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs751683437, ExAC 0.003%). This variant has been observed in individuals with clinical features of Lynch syndrome. Also, it has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 26318770). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 142970). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acid is currently unknown. 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.
GeneDx RCV000656896 SCV000565226 uncertain significance not provided 2018-01-12 criteria provided, single submitter clinical testing This deletion of three nucleotides in MSH6 is denoted c.2561_2563delAGA at the cDNA level and p.Lys854del at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAGA[delAGA]TTAT. Although this variant was observed in a case of possible constitutional mismatch repair deficiency (CMMR-D), sequencing and deletion/duplication of all mismatch repair genes were not performed and therefore this variant may not be responsible for the phenotype (Bougeard 2014). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This in-frame deletion of a single Lysine residue is located in the lever domain (Warren 2007, Kansikas 2010). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH6 Lys854del to be a variant of uncertain significance.
Color Health, Inc RCV000132477 SCV000685296 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656896 SCV000888259 uncertain significance not provided 2018-05-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000202234 SCV001437241 uncertain significance not specified 2020-09-15 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2561_2563delAGA (p.Lys854del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 249108 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2561_2563delAGA has been reported in the literature in individuals affected with possible constitutional mismatch repair deficiency (CMMR-D)/early form of Lynch syndrome (Bougeard_2014) and breast cancer (Hampel_2018, Tung_2014). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Several somatic occurrences of the variant have also been reported in the literature (Gray_2018, Salvador_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000202234 SCV000257223 uncertain significance not specified no assertion criteria provided research
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249963 SCV001423977 likely pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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