Submissions for variant NM_000249.4(MLH1):c.655A>G (p.Ile219Val)

gnomAD frequency: 0.23048  dbSNP: rs1799977

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030230	SCV000106807	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035355	SCV000059003	benign	not specified	2011-08-23	criteria provided, single submitter	clinical testing	This variant is classified as benign based on its high frequency in the general population (rs1799977, MAF >3%).
Eurofins Ntd Llc (ga)	RCV000035355	SCV000110268	benign	not specified	2014-06-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131385	SCV000186361	benign	Hereditary cancer-predisposing syndrome	2014-11-13	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000131385	SCV000292085	benign	Hereditary cancer-predisposing syndrome	2014-11-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000035355	SCV000303152	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000614686	SCV000443330	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034548	SCV000604227	benign	not provided	2023-11-30	criteria provided, single submitter	clinical testing
IntelligeneCG	RCV000144603	SCV000611716	benign	Lynch syndrome 1	2017-08-18	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000614686	SCV000781752	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV001083425	SCV000999981	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000034548	SCV001875389	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24595079, 15918206, 30998989, 28932927, 24728327, 27173243, 27153395, 7704024, 27487738, 9032648, 20336543, 23760103, 20981092, 9697702, 24689082, 22753075, 22949387, 21120944, 17594722, 11555625, 19371218, 22283331, 21239990, 11781295, 16083711, 21136174, 20149637, 19665066, 23403630, 16982745, 17510385, 12810663, 18547406, 19863800, 21615986, 23060557, 22703879, 20860725)
Sema4, Sema4	RCV000131385	SCV002528766	benign	Hereditary cancer-predisposing syndrome	2020-01-10	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000614686	SCV004015862	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000030230	SCV004840890	benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034548	SCV000043321	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030230	SCV000052897	benign	Lynch syndrome	2011-11-15	no assertion criteria provided	clinical testing
ITMI	RCV000035355	SCV000085536	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144603	SCV000189930	benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000035355	SCV000257110	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000035355	SCV000592366	benign	not specified		no assertion criteria provided	clinical testing	The p.Ile219Val variant is not expected to have clinical significance because this residue is not well conserved and the variant amino acid Val (valine) at position 219 is present in frog and zebrafish. In addition, this variant is listed in dbSNP as a common polymorphism (dbSNP#:rs1799977).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000614686	SCV000734264	benign	Colorectal cancer, hereditary nonpolyposis, type 2		no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV001269359	SCV001448700	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000035355	SCV001906103	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000035355	SCV001919475	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000034548	SCV001927690	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000035355	SCV001958956	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000035355	SCV001969492	benign	not specified		no assertion criteria provided	clinical testing