Submissions for variant NM_000249.3(MLH1):c.47T>G (p.Val16Gly) (rs1553637237)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522288	SCV000616777	uncertain significance	not provided	2018-12-11	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.47T>G at the cDNA level, p.Val16Gly (V16G) at the protein level, and results in the change of a Valine to a Glycine (GTG>GGG). This variant was observed in at least one individual with ovarian cancer (Pal 2012). MLH1 Val16Gly was not observed in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Val16Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000546291	SCV000625169	uncertain significance	Hereditary nonpolyposis colon cancer	2017-04-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine with glycine at codon 16 of the MLH1 protein (p.Val16Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000574122	SCV000662069	uncertain significance	Hereditary cancer-predisposing syndrome	2016-06-02	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence

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