ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2213G>A (p.Gly738Glu) (rs148317871)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767194 SCV000211122 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2213G>A at the cDNA level, p.Gly738Glu (G738E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant was observed in an individual with polyposis and in a patient with breast and/or ovarian cancer (Shirts 2016, Cock-Rada 2018). MLH1 Gly738Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the region of interaction with PMS2/MLH3/PMS1 (Raevaara 2005). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Gly738Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
University of Washington Department of Laboratory Medicine,University of Washington RCV000030221 SCV000266179 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000524281 SCV000284052 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 738 of the MLH1 protein (p.Gly738Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs148317871, ExAC 0.01%). This variant has been reported in an individual with colorectal polyposis and a family history of pancreatic cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 36548). 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: "Deleterious"; PolyPhen-2: "Possibly 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.
Counsyl RCV000411992 SCV000488721 uncertain significance Lynch syndrome II 2016-05-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573289 SCV000662026 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000160545 SCV000696152 uncertain significance not specified 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.2213G>A (p.Gly738Glu) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121360 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). This variant has been reported in two patients in literature, one patient with polyposis who had first degree relatives with pancreatic cancer and another with breast and/or ovarian cancer (Shirts_2016, Cock-Rada_2017). No cosegregation and functional study were performed. This variant has also been reported in one internally tested individual who also carried a likely pathogenic MSH2 variant (p.His639Tyr). Multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as uncertain significance. Taken together, this variant is currently classified as 'Variant of Unknown Significance'.

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