ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.971dup (p.Arg325fs) (rs587781554)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129570 SCV000184352 pathogenic Hereditary cancer-predisposing syndrome 2014-01-16 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000767183 SCV000211078 pathogenic not provided 2014-05-14 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted MLH1 c.971dupA at the cDNA level and p.Arg325AlafsX37 (R325AfsX37) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CTGG[A]GCGG. The duplication causes a frameshift, which changes an Arginine to an Alanine at codon 325, and creates a premature stop codon at position 37 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. we consider this variant to be pathogenic.
Invitae RCV000168452 SCV000219149 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-09-26 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 11 of the MLH1 mRNA (c.970_971insA), causing a frameshift at codon 325. This creates a premature translational stop signal (p.Arg325Alafs*37) and is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual with suspected Lynch syndrome (PMID: 25980754). This variant is also known as c.971dupA in the literature. ClinVar contains an entry for this variant (Variation ID: 141177). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781543 SCV000919663 likely pathogenic Lynch syndrome 2018-11-06 criteria provided, single submitter clinical testing Variant summary: MLH1 c.971dupA (p.Arg325AlafsX37) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1210_1211delCT, p.Leu404fsX12; c.1219C>T, p.Gln407X; c.1381A>T, p.Lys461X). The variant was absent in 246132 control chromosomes (gnomAD). The variant, c.971dupA, has been reported in the literature in individuals affected with Lynch Syndrome (Yurgelun 2015, Susswein 2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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