ClinVar Miner

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

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Total submissions: 7
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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 Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000409988 SCV000487998 pathogenic Lynch syndrome II 2015-12-10 criteria provided, single submitter clinical testing
Invitae RCV000524282 SCV000543618 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-18 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075587 SCV000592447 pathogenic Lynch syndrome 2016-10-03 criteria provided, single submitter clinical testing
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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202198 SCV000257091 likely pathogenic not provided no assertion criteria provided research

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