ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1730G>A (p.Arg577His) (rs376220212)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131162 SCV000186106 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000587914 SCV000211347 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1730G>A at the cDNA level, p.Arg577His (R577H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been observed in individuals with breast, endometrial, or pancreatic cancer, as well as in 1/681 healthy individuals undergoing whole genome sequencing (Bodian 2014, Lu 2015, Ring 2016, Yang 2016). Of note, the participants in the whole genome sequencing study were younger than 50 years old thus the unaffected status of this individual may not be significant (Bodian 2014). MSH6 Arg577His was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. MSH6 Arg577His is located in the connector domain (Warren 2007, Kansikas 2011). In-silico analysis, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available information, it is unclear whether MSH6 Arg577His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204422 SCV000260364 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 577 of the MSH6 protein (p.Arg577His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs376220212, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 26689913) and pancreatic cancer (PMID: 27449771). This variant has been reported to co-occur with a pathogenic variant in MSH6 in one individual in the Universal Mutation Database (PMID: 23729658). While it is unknown if these variants are on the same or opposite chromosomes, this observation suggests that the c.1730G>A variant is not a primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 134852). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. However, an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggests that this missense change is likely to be tolerated. Neither of these predictions has 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 RCV000410866 SCV000488474 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-04-14 criteria provided, single submitter clinical testing
Color RCV000131162 SCV000685223 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587914 SCV000695793 uncertain significance not provided 2017-01-16 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1730G>A (p.Arg577His) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 5/120864 control chromosomes at a frequency of 0.0000414, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant was reported in the literature in affected individuals, without strong evidence for causality. Two co-occurrences of the variant of interest and a pathogenic variant have been reported (UMD database MSH6 c.2677_2678delCT, Yang_2016 CDKN2A unspecified mutation), suggesting the variant of interest is not the primary cause of disease in this individual. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence becomes available.
Mendelics RCV000708870 SCV000837886 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
ITMI RCV000121579 SCV000085775 not provided not specified 2013-09-19 no assertion provided reference population

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