ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1601G>A (p.Arg534His) (rs587778523)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656878 SCV000149413 uncertain significance not provided 2017-10-16 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1601G>A at the cDNA level, p.Arg534His (R534H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been identified in one individual with a personal history of colorectal cancer whose tumor showed microsatellite stability and normal immunohistochemistry and one individual with a personal and/or family history suggestive of Lynch syndrome (O?Leary 2014, Kraus 2015). This variant was also identified in 1/50 healthy Central Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. MSH2 Arg534His was observed at an allele frequency of 0.01% (4/30772) in individuals of South Asian ancestry in large population cohorts (Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. MSH2 Arg534His occurs at a position that is not conserved and is located within the Clamp domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Arg534His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000122981 SCV000166264 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 534 of the MSH2 protein (p.Arg534His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs587778523, ExAC 0.01%). This variant has been reported in individuals with colorectal cancer (PMID: 25142776) and breast cancer (PMID: 26824983). ClinVar contains an entry for this variant (Variation ID: 127632). 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, but 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.
Ambry Genetics RCV000492001 SCV000580410 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000492001 SCV000684953 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-21 criteria provided, single submitter clinical testing
Counsyl RCV000662395 SCV000784809 uncertain significance Lynch syndrome I 2016-12-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121559 SCV000917715 uncertain significance not specified 2018-07-19 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1601G>A (p.Arg534His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, clamp domain (IPR007861), which is inserted between the two subdomains of the core domain. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 246194 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (5.3e-05 vs 0.00057), allowing no conclusion about variant significance. c.1601G>A has been reported in the literature in individuals affected with colorectal cancer and in an individual with a positive family history of inherited cancer disorder (Kraus_2015, O'Leary_2014). 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 (MSH2 c.998G>A, p.Cys333Tyr (LOVD)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ITMI RCV000121559 SCV000085753 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000492001 SCV000788030 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-17 no assertion criteria provided clinical testing

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