Submissions for variant NM_000249.4(MLH1):c.503dup (p.Asn168fs)

dbSNP: rs63749959

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075739	SCV000106746	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
GeneDx	RCV000583950	SCV000211076	pathogenic	not provided	2014-03-31	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MLH1 c.503dupA at the cDNA level and p.Asn168LysfsX4 (N168KfsX4) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TAAAAA[A]TCCA. The duplication causes a frameshift, which changes an Asparagine to a Lysine at codon 168, and creates a premature stop codon at position 4 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MLH1 503dupA has been reported in association with Lynch syndrome by Dominguez-Valentin et al. (2013) and is considered pathogenic.
Invitae	RCV000684801	SCV000543603	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-19	criteria provided, single submitter	clinical testing	This variant is also known as 168insA, c.503_504insA, and c.503_4insA. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90250). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of Lynch Syndrome (PMID: 12658575, 15713769, 15849733, 17054581, 24344984). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn168Lysfs*4) 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).
PreventionGenetics, part of Exact Sciences	RCV000583950	SCV000805972	pathogenic	not provided	2018-01-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001187674	SCV001354539	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 6 of the MLH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV001187674	SCV002644382	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-25	criteria provided, single submitter	clinical testing	The c.503dupA pathogenic mutation, located in coding exon 6 of the MLH1 gene, results from a duplication of A at nucleotide position 503, causing a translational frameshift with a predicted alternate stop codon (p.N168Kfs*4). This alteration has been reported in multiple Lynch syndrome families (Wagner A et al. Am. J. Hum. Genet. 2003 May;72:1088-100; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Rossi BM et al. BMC Cancer 2017 Sep;17:623). 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.
Myriad Genetics, Inc.	RCV003452742	SCV004186495	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-14	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000583950	SCV000691848	pathogenic	not provided		no assertion criteria provided	clinical testing
3DMed Clinical Laboratory Inc	RCV000677883	SCV000804044	pathogenic	Carcinoma of colon	2018-03-19	no assertion criteria provided	clinical testing
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249939	SCV001423881	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing