Submissions for variant NM_000249.4(MLH1):c.1411_1414del (p.Lys471Aspfs)

dbSNP: rs63751592

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075201	SCV000106193	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000162473	SCV000212840	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-15	criteria provided, single submitter	clinical testing	The c.1411_1414delAAGA pathogenic mutation, located in coding exon 13 of the MLH1 gene, results from a deletion of 4 nucleotides between positions 1411 and 1414, causing a translational frameshift with a predicted alternate stop codon (p.K471Dfs*19). This well described mutation has been identified in multiple Lynch and suspected-Lynch kindreds (Liu B et al. Nat. Med. Feb 1996:2(2);169-174; Papp J et al. World J. Gastroenterol. 2007 May 21;13(19):2727-32; Goldberg Y et al. Fam Cancer. 2008 Apr;7(4):309-17; Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85; Goldberg Y et al. Fam. Cancer 2014 Mar;13(1):65-73; Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35:1086-1095). 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.
Invitae	RCV000524238	SCV000284019	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys471Aspfs*19) 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: 8574961, 15926618, 17569143, 18389388, 20587412). This variant is also known as c.1410_1413delAAAG. ClinVar contains an entry for this variant (Variation ID: 89727). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000481773	SCV000565153	pathogenic	not provided	2022-07-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Liu et al., 1996; Papp et al., 2007; Sjursen et al., 2010; Goldberg et al., 2014; Yurgelun et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 20587412, 8574961, 25430799, 24689082, 23990280, 18389388, 15926618, 30787465, 28135145, 17569143)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260355	SCV001437296	pathogenic	Hereditary nonpolyposis colon cancer	2020-09-14	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1411_1414delAAGA (p.Lys471AspfsX19) 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. The variant was absent in 251436 control chromosomes (gnomAD). c.1411_1414delAAGA has been reported in the literature in individuals affected with Lynch Syndrome (example: Hansen_2014, Liu_1996, Yurgelun_2017, Goldberg_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) and an expert panel (InSiGHT) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003451026	SCV004190035	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003451026	SCV004195076	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-03	criteria provided, single submitter	clinical testing