ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1268G>A (p.Arg423Lys) (rs370687064)

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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 RCV000131167 SCV000186112 likely benign Hereditary cancer-predisposing syndrome 2017-12-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign)
Color RCV000131167 SCV000906463 benign Hereditary cancer-predisposing syndrome 2016-04-27 criteria provided, single submitter clinical testing
Counsyl RCV000411892 SCV000488386 uncertain significance Lynch syndrome II 2016-03-15 criteria provided, single submitter clinical testing
GeneDx RCV000588087 SCV000570384 uncertain significance not provided 2016-05-18 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1268G>A at the cDNA level, p.Arg423Lys (R423K) at the protein level, and results in the change of an Arginine to a Lysine (AGG>AAG). This variant has been reported at least once, in an individual diagnosed with an early-onset colorectal cancer that demonstrated microsatellite instability (MSI-H) and loss of the MLH1 protein by tumor immunohistochemistry (IHC) (Hardt 2011). MLH1 Arg423Lys was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. MLH1 Arg423Lys occurs at a position that is not conserved and is located within a region of interaction with EXO1 (UniProt). 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 Arg423Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588087 SCV000696102 uncertain significance not provided 2016-06-10 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1268G>A (p.Arg423Lys) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant . This variant was found in 4/121390 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). One reputable database (UMD) reported a patient carries the variant of interest and MLH1 c.676C>T (p.Arg226X, classified pathogenic in ClinVar), suggesting the variant of interest may not associate with the disease. In addition, multiple clinical diagnostic laboratories/reputable databases provided conflicting classifications: likely benign and VUS. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV000122970 SCV000166243 likely benign Hereditary nonpolyposis colon cancer 2017-11-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000487001 SCV000713006 uncertain significance not specified 2017-04-17 criteria provided, single submitter clinical testing The p.Arg423Lys variant in MLH1 has not been previously reported in individuals with Lynch syndrome, but has been reported in ClinVar (Variation ID 135846). Thi s variant has also been identified in 4/66720 of European chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3706870 64). Computational prediction tools and conservation analysis suggest that the p .Arg423Lys variant may not impact the protein, though this information is not pr edictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Arg423Lys variant is uncertain.

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