ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.926C>G (p.Ser309Cys) (rs544222338)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656891 SCV000149355 uncertain significance not provided 2020-12-19 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28873162, 31307542)
Ambry Genetics RCV000115446 SCV000215268 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-07 criteria provided, single submitter clinical testing The p.S309C variant (also known as c.926C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 926. The serine at codon 309 is replaced by cysteine, an amino acid with dissimilar properties. 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.
Invitae RCV001089225 SCV000283860 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212637 SCV000601622 uncertain significance not specified 2016-12-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115446 SCV000902781 likely benign Hereditary cancer-predisposing syndrome 2016-11-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212637 SCV001360587 likely benign not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: MSH6 c.926C>G (p.Ser309Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 251308 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Non-Polyposis Colon Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.926C>G has been reported in the literature in individual(s) affected with advanced cancer (Mandelker_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as likely benign (2x) and uncertain significance (4x). Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353732 SCV000592578 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Ser309Cys variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from individuals with advanced cancer (Mandelker 2017). The variant was identified in dbSNP (rs544222338) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics and likely benign by Color and Invitae) and UMD-LSDB (observed 1x). The variant was identified in control databases in 75 of 277,020 chromosomes (1 homozygous) at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24,004 chromosomes (freq: 0.00004), European in 3 of 126,576 chromosomes (freq: 0.00002) and South Asian in 71 of 30,780 chromosomes (freq: 0.002). The variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Ser309Cys residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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