ClinVar Miner

Submissions for variant NM_001167617.2(MLH1):c.1958_1959del (p.Lys653fs) (rs267607901)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000490564 SCV000106583 pathogenic Lynch syndrome I 2014-10-10 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000213486 SCV000277425 pathogenic Hereditary cancer-predisposing syndrome 2018-01-11 criteria provided, single submitter clinical testing The c.2252_2253delAA pathogenic mutation, located in coding exon 19 of the MLH1 gene, results from a deletion of two nucleotides at nucleotide positions 2252 to 2253, causing a translational frameshift with a predicted alternate stop codon (p.K751Sfs*3). This mutation has been identified in numerous individuals with features of Lynch syndrome (Sheng JQ et al, Cytogenet. Genome Res. 2008 ; 122(1):22-7; Nilbert M et al, Fam. Cancer 2009 ; 8(1):75-83; Han HJ et al, J. Natl. Cancer Inst. 1996 Sep; 88(18):1317-9; Cajal AR et al. Medicina (B Aires), 2016;76:180-2). Borelli, et al. describes this as an Italian founder mutation and demonstrates that it segregates with disease in 11 families (10 meeting Amsterdam criteria) with a total of 24 MSI-H tumors (Borelli I et al, Fam. Cancer 2014 Sep; 13(3):401-13).This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Counsyl RCV000409988 SCV000487998 pathogenic Lynch syndrome II 2015-12-10 criteria provided, single submitter clinical testing
Invitae RCV000524282 SCV000543618 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-06-21 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 19 of the MLH1 mRNA (c.2252_2253delAA), causing a frameshift at codon 751. This creates a premature translational stop signal in the last exon of the MLH1 mRNA (p.Lys751Serfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acids of the MLH1 protein. This variant is not present in population databases (ExAC no frequency). This variant is a known Italian Lynch syndrome founder mutation (PMID: 24802709), which has also been reported in affected individuals from other populations (PMID: 8797773, 27295708, 18566915, 18931482). ClinVar contains an entry for this variant (Variation ID: 90101). While no functional studies have been performed to test the effect of this particular variant on MLH1 protein function or stability, it affects the highly conserved C-terminal domain (CTD) responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000202198 SCV000778966 pathogenic not provided 2018-01-23 criteria provided, single submitter clinical testing This deletion of two nucleotides in MLH1 is denoted c.2252_2253delAA at the cDNA level and p.Lys751SerfsX3 (K751SfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TACA[delAA]GTCT. The deletion causes a frameshift which changes a Lysine to a Serine at codon 751, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. MLH1 c.2252_2253delAA has been reported in individuals with Lynch syndrome-associated cancers, with many tumors showing loss of PMS2 protein expression on immunohistochemistry (IHC), as well as in multiple families meeting Amsterdam criteria, segregating with Lynch syndrome-associated cancer in at least seven families (Han 1996, Nilbert 2009, Bonadona 2011, Borelli 2014, Cajal 2016, Cloyd 2017, Pearlman 2017). MLH1 c.2252_2253delAA is considered to be an Italian founder variant (Borelli 2014), and the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). We consider this variant to be pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000409988 SCV001434927 pathogenic Lynch syndrome II 2018-10-12 criteria provided, single submitter clinical testing This c.2252_2253delAA (p.Lys751Serfs*3) variant in the MLH1 gene has been reported in multiple individuals with Lynch syndrome (PMID 8797773, 24802709, 27295708, 28874130). Microsatellite instability (MSI) and protein expression studies in tumors from patients with this variant showed MSI-high mutator phenotype and loss of PMS2 expression (PMID 24802709). This variant is absent from large databases of genetic variation in the general population. Therefore, the c.2252_2253delAA (p.Lys751Serfs*3) variant in the MLH1 gene is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202198 SCV000257091 likely pathogenic not provided no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075587 SCV000592447 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MLH1 p.Lys751SerfsX3 variant was identified in 14 of 2728 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer, and was not identified in 924 control chromosomes from healthy individuals (Borelli 2014, Han 1996, Nilbert 2009, Shin 2004). The variant was also identified in dbSNP (ID: rs267607907) as “With Pathogenic allele”, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as uncertain significance by InSight, pathogenic by Ambry genetics, likely pathogenic by Mayo clinic). The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. The c.2252_2253del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 751 and leads to a premature stop codon 3 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MLH1 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. A study by Borelli (2014) identified 11 patients with colorectal cancer with this variant and showed the MSI-high mutator phenotype with loss of PMS2 expression in all but one tumor. There was also a statistically significant (p = 0.0057) higher frequency of pancreatic tumours compared to families with other MLH1 pathogenic variants. Moreover the clinical features, tissue analysis and co-segregation with disease strongly support the hypothesis that the MLH1 c.2252_2253delAA variant has a pathogenic effect. In addition, in an in silico model study the variant fell in the >99% probability range for known class 5 (pathogenic) variant (Joeri van der Velde 2015). The c-terminus of the MLH1 protein is known to be well conserved and important for PMS2 binding and DNA mismatch repair (Mohd 2006). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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