ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3980A>G (p.Asn1327Ser) (rs780187989)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205455 SCV000261920 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1327 of the MSH6 protein (p.Asn1327Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs780187989, ExAC 0.07%). This variant has been reported in individuals affected with breast cancer, ovarian cancer and colorectal cancer (PMID:30093976, 23047549, 30521064). ClinVar contains an entry for this variant (Variation ID: 220943). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000217289 SCV000275657 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-10 criteria provided, single submitter clinical testing The p.N1327S variant (also known as c.3980A>G), located in coding exon 9 of the MSH6 gene, results from an A to G substitution at nucleotide position 3980. The asparagine at codon 1327 is replaced by serine, an amino acid with highly similar properties. This alteration was detected at least once in a cohort of 1893 women with epithelial ovarian cancer from three population-based studies who were ascertained for mutations in MLH1, MSH2 and MSH6 (Pal T et al. Br. J. Cancer, 2012 Nov;107:1783-90). This amino acid position is poorly 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 RCV001711360 SCV000616793 likely benign not provided 2018-12-12 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23047549, 30521064, 30093976)
Color Health, Inc RCV000217289 SCV000685472 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-07 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000519500 SCV000967445 uncertain significance not specified 2018-10-16 criteria provided, single submitter clinical testing The p.Asn1327Ser variant in MSH6 has been reported in one individual with ovaria n cancer (Pal 2012) and has also been reported by other clinical laboratories in ClinVar (Variation ID: 220943). Additionally, it has been identified in 16/1874 0 East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computati onal prediction tools and conservation analysis suggest that the p.Asn1327Ser va riant may not impact the protein. In summary, the clinical significance of the p.Asn1327Ser variant is uncertain. ACMG/AMP Criteria applied: BP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000519500 SCV001339045 likely benign not specified 2021-08-29 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3980A>G (p.Asn1327Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 246806 control chromosomes, predominantly at a frequency of 0.00093 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.3980A>G has been reported in the literature in at least one individual affected with Lynch Syndrome (Jiang_2019), as well as a VUS in settings of multigene panel testing among individuals affected with epithelial ovarian cancer (Pal_2012) and breast cancer (Chan_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. 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. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.

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