Submissions for variant NM_000249.4(MLH1):c.1855del (p.Ala619fs)

dbSNP: rs63749986

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075388	SCV000106382	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000217973	SCV000277947	pathogenic	Hereditary cancer-predisposing syndrome	2017-11-28	criteria provided, single submitter	clinical testing	The c.1855delG pathogenic mutation, located in coding exon 16 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 1855, causing a translational frameshift with a predicted alternate stop codon (p.A619Lfs*18). This pathogenic mutation has been reported in multiple Hispanic individuals meeting Lynch syndrome diagnostic criteria (Giraldo A et al. Fam. Cancer. 2005;4:285-90; Cruz-Correa M et al. Fam. Cancer. 2015 Sep;14:415-25). 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	RCV000798031	SCV000937624	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-31	criteria provided, single submitter	clinical testing	This variant is also known as c.1856delG. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 16341804, 25782445). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala619Leufs*18) 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). ClinVar contains an entry for this variant (Variation ID: 89910). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000217973	SCV001345309	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 16 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 been reported in individuals and families affected with Lynch syndrome (PMID: 16341804, 28874130), and in an individual with early-onset colorectal cancer who had a family history of colorectal cancer (PMID: 25782445). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260354	SCV001437295	pathogenic	Hereditary nonpolyposis colon cancer	2020-09-14	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1855delG (p.Ala619LeufsX18) 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 251414 control chromosomes (gnomAD). c.1855delG has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Giraldo_2005, Cruz-Correa_2015). These data indicate that the variant may 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.
PreventionGenetics, part of Exact Sciences	RCV003390767	SCV004121556	pathogenic	MLH1-related disorder	2022-10-12	criteria provided, single submitter	clinical testing	The MLH1 c.1855delG variant is predicted to result in a frameshift and premature protein termination (p.Ala619Leufs*18). This variant has been previously reported in individuals with hereditary nonpolyposis colorectal cancer or Lynch syndrome (Giraldo et al. 2005. PubMed ID: 16341804, reported as 1856delG; Table 3, Rossi et al. 2017. PubMed ID: 28874130). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar this variant is reported as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/89910/). Frameshift variants in MLH1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Myriad Genetics, Inc.	RCV003451074	SCV004186311	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.