ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1063G>A (p.Gly355Ser) (rs587778531)

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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 RCV000130273 SCV000185118 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000588001 SCV000211273 uncertain significance not provided 2017-12-04 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1063G>A at the cDNA level, p.Gly355Ser (G355S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant has been reported in two related individuals with non-medullary thyroid cancer (Yu 2015), and in an Asian patient with early-onset colorectal cancer (DeRycke 2017). This variant was also observed in 1/62 healthy East 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. MSH6 Gly355Ser was observed at an allele frequency of 0.15% (29/18,868) in individuals of East Asian ancestry in large population cohorts (Lek 2016). Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Gly355Ser is located within the nuclear localization signals (Gassman 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Gly355Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000409146 SCV000488049 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-18 criteria provided, single submitter clinical testing
Invitae RCV000588001 SCV000561488 likely benign not provided 2019-02-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515340 SCV000611403 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2017-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121578 SCV000695770 likely benign not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1063G>A (p.Gly355Ser) results in a non-conservative amino acid change in the encoded protein sequence. 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 0.00012 in 276930 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.1063G>A, has been reported in the literature in an individual affected with familial non-medullary thyroid cancer (Yu_2015). This report does not provide an unequivocal conclusion about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance" (4x) and "likely benign" (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV000130273 SCV000910734 likely benign Hereditary cancer-predisposing syndrome 2016-04-22 criteria provided, single submitter clinical testing
ITMI RCV000121578 SCV000085774 not provided not specified 2013-09-19 no assertion provided reference population

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