Submissions for variant NM_000179.2(MSH6):c.3836G>A (p.Ser1279Asn) (rs864622400)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205628	SCV000260488	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces serine with asparagine at codon 1279 of the MSH6 protein (p.Ser1279Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 220159). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV000481950	SCV000565236	uncertain significance	not provided	2017-05-31	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3836G>A at the cDNA level, p.Ser1279Asn (S1279N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser1279Asn was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ser1279Asn occurs at a position that is conserved across species and is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Ser1279Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000562735	SCV000662359	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-24	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence
Color	RCV000562735	SCV000685449	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000662811	SCV000785646	uncertain significance	Hereditary nonpolyposis colorectal cancer type 5	2017-10-18	criteria provided, single submitter	clinical testing

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