ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3482CTG[1] (p.Ala1162del) (rs63751427)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128906 SCV000172773 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-21 criteria provided, single submitter clinical testing The c.3485_3487delCTG variant (also known as p.A1162del) is located in coding exon 6 of the MSH6 gene. This alteration results from the deletion of 3 nucleotides at positions 3485 to 3487, causing the deletion of a highly-conserved alanine residue at codon 1162. The amino acid resides in a well-defined functional domain and is adjacent to a helix that contains the MSH6 ATP binding p-loop (Warren JJ et al. Mol. Cell 2007 May;26(4):579-92). This alteration has been identified in three individuals with endometrial cancer and ages at diagnosis ranged from 45y to 54y. One of the individuals was also diagnosed with rectal cancer at the age of 60y. Tumor results for two of the individuals revealed loss of MSH6 protein expression on immunohistochemistry while the third individual had a family history that met Amsterdam criteria (Ambry internal data). The alteration was also reported in a patient with endometrial cancer and rectal cancer diagnosed at the ages of 53y and 61y, respectively. Furthermore, tumor results from the endometrial cancer revealed microsatellite instability (MSI-H) (Goodfellow PJ et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100(10: 5908-13). In addition, this alteration is predicted to be deleterious by PROVEAN in silico analysis (Choi Y et al. PLoS ONE 2012 ; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000484286 SCV000568726 uncertain significance not provided 2016-12-07 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides in MSH6 is denoted c.3485_3487delCTG at the cDNA level and p.Ala1162del (A1162del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CCTG[delCTG]AAGT. This deletion occurs in a region that is conserved across species and is located in domain V of the MutS domain (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. 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 Ala1162del to be a variant of uncertain significance.
Invitae RCV000542403 SCV000624874 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-10-30 criteria provided, single submitter clinical testing This variant, c.3485_3487delCTG, results in the deletion of 1 amino acid of the MSH6 protein (p.Ala1162del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with suspected Lynch syndrome (PMID: 22658618, 28514183). ClinVar contains an entry for this variant (Variation ID: 140774). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted 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.
Color Health, Inc RCV000128906 SCV000908422 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-14 criteria provided, single submitter clinical testing

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