ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205455 SCV000261920 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 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 an individual affected with ovarian cancer (PMID: 23047549). 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 2017-11-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000519500 SCV000616793 uncertain significance not specified 2017-08-10 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3980A>G at the cDNA level, p.Asn1327Ser (N1327S) at the proteinlevel, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been observed in at leastone individual with ovarian cancer (Pal 2012). MSH6 Asn1327Ser was observed at an allele frequency of 0.072%(6/8328) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000Genomes Consortium 2015, Lek 2016). Since Asparagine and Serine share similar properties, this is considered aconservative amino acid substitution. MSH6 Asn1327Ser occurs at a position that is not conserved and is locatedwithin the ATPase domain and an MSH2 binding site (Kariola 2002, Kansikas 2011, Warren 2007). In silico analysesare inconsistent regarding the effect this variant may have on protein structure and function. Based on currentlyavailable information, it is unclear whether MSH6 Asn1327Ser is pathogenic or benign. We consider it to be a variantof uncertain significance
Color RCV000217289 SCV000685472 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-14 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.

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