Submissions for variant NM_000249.4(MLH1):c.210_213del

dbSNP: rs267607723

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075546	SCV000106523	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000793513	SCV000932869	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-06-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 90061). This variant is also known as Del AGAA at n 210 and a 4-bp deletion affecting positions +2, +1, 208 and 209. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 11112663, 15235038, 15879014, 16830052, 27064304). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu71Ilefs*20) 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).
Ambry Genetics	RCV001014440	SCV001175146	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-27	criteria provided, single submitter	clinical testing	The c.210_213delAGAA pathogenic mutation, located in coding exon 3 of the MLH1 gene, results from a deletion of 4 nucleotides at nucleotide positions 210 to 213, causing a translational frameshift with a predicted alternate stop codon (p.E71Ifs*20). This alteration has been reported in multiple families that either met Amsterdam criteria or Bethesda guidelines for testing of hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (Scott RJ et al. Am. J. Hum. Genet., 2001 Jan;68:118-127; Zavodna K et al. Neoplasma 2006;53:269-76; Sjursen W et al. Mol. Genet. Genomic Med. 2016 Mar;4:223-31). RNA studies have also shown that this mutation leads to exon 3 skipping of MLH1 (Renkonen E et al. J. Med. Genet. 2004 Jul;41:e95; Ambry internal data). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation, aberrant splicing or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001014440	SCV002053622	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-22	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides from exon 3 of the MLH11 gene, creating a frameshift and a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. In addition, this variant is predicted to weaken intron 2 splice acceptor site by splice prediction tools and has been reported to cause in-frame skipping of exon 3 (PMID: 15235038). This variant has been detected in seven families affected with Lynch syndrome (PMID: 11112663, 15235038, 15879014, 16830052, 27064304). 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.
Myriad Genetics, Inc.	RCV003451107	SCV004186295	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.