ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1937A>G (p.Lys646Arg) (rs201096652)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229693 SCV000283737 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 646 of the MSH6 protein (p.Lys646Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs201096652, ExAC 0.07%). This variant has been observed in individual(s) with endometrial and breast cancers (PMID: 31307542, 26689913). ClinVar contains an entry for this variant (Variation ID: 237148). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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 RCV000482874 SCV000565219 uncertain significance not provided 2018-02-21 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1937A>G at the cDNA level, p.Lys646Arg (K646R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant has been reported in an individual with breast cancer (Lu 2015). MSH6 Lys646Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Lys646Arg is located in the connector domain (Warren 2007, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Lys646Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491214 SCV000580205 likely benign Hereditary cancer-predisposing syndrome 2018-07-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (benign);Structural Evidence
Color RCV000491214 SCV000685240 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482874 SCV001134402 uncertain significance not provided 2019-06-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192456 SCV001360592 uncertain significance not specified 2019-07-18 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1937A>G (p.Lys646Arg) results in a conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function, in addition, a bioinformatics tool developed to predict the impact of missense variants in MSH6, indicated no impact on protein function (Terui 2013). The variant allele was found at a frequency of 3.6e-05 in 251204 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.00043 in the gnomAD database, which is higher than the expected maximum for a pathogenic variant in MSH6 (0.00014), supporting a benign role for the variant. c.1937A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (Lu_2015, Wang_2019, Samuel_2019, Yehia_2018), and one of these individuals had a positive family history for colon cancer (Samuel_2019). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH6, p.K1228fs*2), providing supporting evidence for a benign role (Yehia_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (3x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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