Submissions for variant NM_000179.3(MSH6):c.1565A>G (p.Gln522Arg)

gnomAD frequency: 0.00001  dbSNP: rs63751009

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214996	SCV000276335	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-19	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 this alteration remains unclear.
GeneDx	RCV000219119	SCV000279097	uncertain significance	not provided	2023-04-04	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; 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 et al., 2002; Domingo et al., 2005; Niessen et al., 2006); This variant is associated with the following publications: (PMID: 26333163, 11709755, 15782118, 24100870, 16636019, 18790734, 17531815, 21120944, 22102614)
Invitae	RCV000556355	SCV000624666	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000662803	SCV000785627	uncertain significance	Lynch syndrome 5	2017-10-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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.
Sema4, Sema4	RCV000214996	SCV002535636	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662803	SCV004019093	uncertain significance	Lynch syndrome 5	2023-03-30	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	RCV003460663	SCV004195761	uncertain significance	Endometrial carcinoma	2023-05-28	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000662803	SCV001749797	not provided	Lynch syndrome 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.