ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1565A>G (p.Gln522Arg) (rs63751009)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214996 SCV000276335 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-18 criteria provided, single submitter clinical testing The p.Q522R variant (also known as c.1565A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1565. The glutamine at codon 522 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in multiple early-onset colorectal patients, including two whose tumors demonstrated intact MSH6 expression by IHC analysis (Berends MJ et al. Am. J. Hum. Genet. 2002 Jan; 70(1):26-37; Domingo E et al. Oncogene 2005 Jun; 24(24):3995-8; Niessen RC et al. Gut 2006 Dec; 55(12):1781-8). In an in vitro MMR assay, p.Q522R was classified as repair proficient due to its repair efficiency being significantly higher than repair-deficient controls (Drost M et al. Hum. Mutat. 2012 Mar; 33(3):488-94). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.Q522R remains unclear.
GeneDx RCV000219119 SCV000279097 uncertain significance not provided 2016-03-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1565A>G at the cDNA level, p.Gln522Arg (Q522R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). MSH6 Gln522Arg demonstrated significantly higher mismatch repair (MMR) activity in an in vitro MMR cell-free assay compared to repair-deficient controls (Drost 2012). This variant has been observed in at least four cases of early-onset colorectal cancers, most exhibiting normal MSI and/or IHC analyses, with no corresponding family having met Amsterdam I or II criteria for Lynch Syndrome (Berends 2002, Domingo 2005, Niessen 2006). MSH6 Gln522Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Gln522Arg occurs at a position that is conserved across species and is located at the MSH2 binding site and in domain II of the MutS domain (Kariola 2002, Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Gln522Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000556355 SCV000624666 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-02 criteria provided, single submitter clinical testing
Counsyl RCV000662803 SCV000785627 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-10-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000214996 SCV000903942 likely benign Hereditary cancer-predisposing syndrome 2016-10-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194395 SCV001363903 uncertain significance not specified 2019-10-10 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1565A>G (p.Gln522Arg) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695). Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251306 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1565A>G has been reported in the literature in at least 3 individuals affected with colorectal cancer, however the associated tumors in 2 of these cases were noted to be microsatellite stable (Berends_2002, Domingo_2005). These reports therefore do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Experimental evidence evaluating an impact on protein function demonstrated the variant protein has a repair efficiency that was significantly higher than repair-deficient controls (~75% of the wild-type), therefore was concluded to be repair proficient in this assay (Drost_2012). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (4x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
GenomeConnect - Invitae Patient Insights Network RCV000662803 SCV001749797 not provided Hereditary nonpolyposis colorectal cancer type 5 no assertion provided phenotyping only Variant interpreted as Likely benign and reported on 09-17-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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