ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.626A>G (p.Asn209Ser) (rs150478207)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132489 SCV000187583 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000132489 SCV000902912 likely benign Hereditary cancer-predisposing syndrome 2016-04-22 criteria provided, single submitter clinical testing
Counsyl RCV000662374 SCV000784768 uncertain significance Lynch syndrome II 2017-04-27 criteria provided, single submitter clinical testing
GeneDx RCV000480315 SCV000566134 uncertain significance not provided 2019-01-09 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.626A>G at the cDNA level, p.Asn209Ser (N209S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been observed in at least one individual with ovarian cancer (Pal 2012). MLH1 Asn209Ser was observed at an allele frequency of 0.038% (4/10,392) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. MLH1 Asn209Ser occurs at a position that is not conserved and is located in the N-terminal ATPase domain (Andersen 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MLH1 Asn209Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000200318 SCV000254371 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 209 of the MLH1 protein (p.Asn209Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs150478207, ExAC 0.04%). This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 142980). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The serine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
Mendelics RCV000708915 SCV000837999 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480315 SCV000889401 uncertain significance not provided 2018-02-23 criteria provided, single submitter clinical testing

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