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 2019-12-11 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 ovarian cancer and colorectal cancer (PMID: 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 2015-05-08 criteria provided, single submitter clinical testing 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 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.
Integrated Genetics/Laboratory Corporation of America RCV000519500 SCV001339045 likely benign not specified 2020-03-20 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 6.5- fold 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. c.3980A>G has been reported in the literature in at least one individual affected with Lynch Syndrome (Jiang_2019), as well as individuals affected with epithelial ovarian cancer (Pal_2012) and breast cancer (Chan_2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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