Submissions for variant NM_000249.4(MLH1):c.971dup (p.Arg325fs)

dbSNP: rs587781554

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129570	SCV000184352	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-01	criteria provided, single submitter	clinical testing	The c.971dupA pathogenic mutation, located in coding exon 11 of the MLH1 gene, results from a duplication of A at nucleotide position 971, causing a translational frameshift with a predicted alternate stop codon (p.R325Afs*37). This mutation has been identified in multiple cohorts of individuals undergoing NGS panel testing for hereditary cancer, including at least one individual with a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20; Susswein LR et al. Genet. Med., 2016 08;18:823-32; Espenschied CR et al. J. Clin. Oncol., 2017 Aug;35:2568-2575). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg325Alafs*37) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 25980754). This variant is also known as c.971dupA. ClinVar contains an entry for this variant (Variation ID: 141177). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Myriad Genetics, Inc.	RCV003453065	SCV004189849	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.