Submissions for variant NM_000249.4(MLH1):c.1151T>A (p.Val384Asp)

gnomAD frequency: 0.00077  dbSNP: rs63750447

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075123	SCV000106114	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Invitae	RCV001081259	SCV000166240	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000121360	SCV000170294	benign	not specified	2013-10-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000129936	SCV000184754	benign	Hereditary cancer-predisposing syndrome	2014-11-18	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.
PreventionGenetics, part of Exact Sciences	RCV000121360	SCV000303143	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000662558	SCV000443333	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121360	SCV000539632	benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 3.9% East Asian chromosomes
Genetic Services Laboratory, University of Chicago	RCV000121360	SCV000595802	benign	not specified	2019-02-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129936	SCV000684719	benign	Hereditary cancer-predisposing syndrome	2015-04-07	criteria provided, single submitter	clinical testing
Counsyl	RCV000662558	SCV000785156	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2017-05-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000755644	SCV000883043	likely benign	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2022-05-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129936	SCV002528627	benign	Hereditary cancer-predisposing syndrome	2020-05-27	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121360	SCV002760286	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149604	SCV003838210	benign	Breast and/or ovarian cancer	2022-02-08	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000662558	SCV004015887	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034537	SCV004185049	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	MLH1: BS1, BS2
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034537	SCV000043322	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000121360	SCV000085541	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144609	SCV000189936	benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Database of Curated Mutations (DoCM)	RCV000437810	SCV000504967	likely pathogenic	Lung adenocarcinoma	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420168	SCV000504968	likely pathogenic	Gastric adenocarcinoma	2015-07-14	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353661	SCV000592396	benign	Bile duct cancer		no assertion criteria provided	clinical testing	The MLH1 p.Val384Asp variant was identified in the literature and by our laboratory. It was identified in 104 of 3286 proband chromosomes (allele frequency 0.03) with different cancer types including colon, pancreatic and lung; and was identified in 53 of 2818 race-matched control chromosomes (allele frequency 0.03), increasing the likelihood that this is a benign variant in certain populations of origin (Chao 2008, Fan 2007, Kim 2010, Kim 2004, Ku 2002, Li 2005 , Lee 2005, Mei 2006, Ohsawa 2009, Shi 2003, Wang 2007, Wang 1998, Yan 2008 , Yap 2009, Yuan 2004,). The variant was also identified in dbSNP (ID: rs63750447) with a minor allele frequency of 0.009 (1000 Genomes Project), COSMIC, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, ClinVar database, and UMD (2X as a neutral variant). The variant was identified in co-occurrence with pathogenic MLH1 variants by Lee (2005) (c.1459C > T (p.Arg487X)), by our laboratory (c.453+1G>T, r.spl?), and in a sample submitted to UMD (c.453+1G>T), increasing the likelihood that the p.Val384Asp variant does not have clinical importance. In addition, based on a personal communication with the Pathology Department of the University of Hong Kong, sequencing on normal population DNA from their locality (108 normal blood DNA), this variant was found in 7 individuals and was regarded as a non-pathogenic variant. Furthermore, the variant was classified as benign by 4 submitters to the ClinVar database: InSiGHT (reviewed by expert panel), GeneDX, Ambry Genetics, and the Biesecker Laboratory – ClinSeq Project. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000121360	SCV001977734	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000121360	SCV001979021	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000121360	SCV002036468	benign	not specified		no assertion criteria provided	clinical testing