ClinVar Miner

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

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Total submissions: 10
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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 2018-10-25 criteria provided, single submitter clinical testing The p.G355S variant (also known as c.1063G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1063. The glycine at codon 355 is replaced by serine, an amino acid with similar properties. This variant was identified in one individual of East Asian descent in a cohort of 681 healthy, ancestrally diverse individuals (Bodian DL et al. PLoS ONE. 2014 Apr;9:e94554). It was also identified in 2 out of 3 family members with non-medullary thyroid cancer (Yu Y et al. Sci Rep. 2015 Nov;5:16129.). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 RCV001083152 SCV000561488 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-03 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc RCV000130273 SCV000910734 likely benign Hereditary cancer-predisposing syndrome 2016-04-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588001 SCV001469562 likely benign not provided 2020-07-08 criteria provided, single submitter clinical testing
ITMI RCV000121578 SCV000085774 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356010 SCV001551057 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH6 p.Gly355Ser variant was identified in 1 of 76 proband chromosomes (frequency: 0.01) from individuals or families with familial or sporadic non-medullary thyroid cancer, being identified in 2 affected members of the same family; and in 1 of 1362 chromosomes from healthy individuals (frequency: 0.0007) (Yu_2015_26530882, Bodian_2014_24728327). The variant was also identified in dbSNP (ID: rs587778531) “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: likely benign by Invitae, uncertain significance by Ambry Genetics, GeneDx, Counsyl, Fulgent Genetics, and classification not provided by ITMI), Clinvitae (4x), Insight Hereditary Tumors Database (1x). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 33 of 276930 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 1 of 6466 chromosomes (freq: 0.0002), East Asian in 29 of 18868 chromosomes (freq: 0.002), and South Asian in 3 of 30782 chromosomes (freq: 0.0001) while not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish and European Finnish populations. The p.Gly355 residue is conserved in mammals but not in more distantly related organisms; however, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood that the Ser residue impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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