ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2027A>G (p.Lys676Arg) (rs143643688)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131641 SCV000186666 likely benign Hereditary cancer-predisposing syndrome 2019-04-09 criteria provided, single submitter clinical testing Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ;Insufficient or conflicting evidence;In silico models in agreement (benign) ;Other data supporting benign classification;Structural Evidence;No disease association in small case-control study
GeneDx RCV000212656 SCV000211287 uncertain significance not provided 2016-11-18 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2027A>G at the cDNA level, p.Lys676Arg (K676R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Lys676Arg was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. MSH6 Lys676Arg occurs at a position that is not conserved and is located within the MutS domain II (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 Lys676Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000204601 SCV000261183 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 676 of the MSH6 protein (p.Lys676Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs143643688, ExAC 0.006%). This variant has been reported in individuals affected with breast cancer (PMID: 25186627) and pancreatic cancer (PMID: 25479140). ClinVar contains an entry for this variant (Variation ID: 142496). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 protein (PMID: 23621914), all suggest that this missense change is likely to be tolerated. The arginine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
Counsyl RCV000410949 SCV000489141 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-23 criteria provided, single submitter clinical testing
Color RCV000131641 SCV000902971 likely benign Hereditary cancer-predisposing syndrome 2015-11-08 criteria provided, single submitter clinical testing

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