Submissions for variant NM_000249.4(MLH1):c.1217G>A (p.Ser406Asn)

gnomAD frequency: 0.00087  dbSNP: rs41294980

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075152	SCV000106144	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
Invitae	RCV001079932	SCV000166242	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000121359	SCV000170295	benign	not specified	2013-12-19	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	RCV000130336	SCV000185186	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.
Eurofins Ntd Llc (ga)	RCV000121359	SCV000225492	likely benign	not specified	2014-11-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121359	SCV000539640	uncertain significance	not specified	2017-01-10	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: This variant is present at 0.13% in gnomAD (171/126520 European chrs). It is classified in ClinVar with 3 stars as Likely benign or benign by InSiGHT (Expert panel), Invitae, GeneDx, Ambry, Emory, Mayo, and as VUS by Biesecker lab. It is not a poorly conserved AA but no species has Asn at this position. It is present in 15 papers in HGMD (classified as DM?), most comments say it is not pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000130336	SCV000684730	likely benign	Hereditary cancer-predisposing syndrome	2015-04-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034539	SCV000696101	benign	not provided	2016-03-07	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.1217G>A variant affects a non-conserved nucleotide, resulting in an amino acid change from Ser to Asn. 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index). In vitro MMR assay has shown that this variant has ~75% of wild-type activity and interacts with EXO1 and PMS2 similar to wild-type in a yeast two-hybrid assay. This variant is found in 115/123542 control chromosomes at a frequency of 0.0009309, which exceeds the maximal expected frequency of a pathogenic allele (0.0007105). Additionally, multiple reputable diagnostic labs and databases have classified this variant as benign/neutral. Taken together, this variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000034539	SCV000805944	likely benign	not provided	2017-04-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000987170	SCV001136403	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034539	SCV001153841	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MLH1: BP4, BS3:Moderate, BS1
Illumina Laboratory Services, Illumina	RCV000987170	SCV001307796	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-11-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034539	SCV002009378	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798062	SCV002042071	likely benign	Breast and/or ovarian cancer	2022-10-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121359	SCV002071028	likely benign	not specified	2021-09-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130336	SCV002528633	benign	Hereditary cancer-predisposing syndrome	2020-11-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121359	SCV002552490	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496516	SCV002812546	likely benign	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2022-01-10	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000987170	SCV004015876	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	RCV000075152	SCV004840975	likely benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130336	SCV005045371	benign	Hereditary cancer-predisposing syndrome	2024-04-16	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034539	SCV000043324	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000121359	SCV000085540	not provided	not specified	2013-09-19	no assertion provided	reference population
Mayo Clinic Laboratories, Mayo Clinic	RCV000121359	SCV000257048	benign	not specified		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353546	SCV000592400	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	 The MLH1 p.Ser406Asn variant was identified in 6 of 4978 proband chromosomes (frequency: 0.001) from Danish, Spanish, Scottish, Korean, Italian and American individuals or families with  HNPCC, or sporadic CRC (Nilbert 2009, Martinez-Bouzas 2009, Kim 2004, Cunningham 2001, Perez-Cabornero 2013, Genuardi  1999, Barnetson 2008). Multiple functional assays  show the variant to be MMR proficient (Drost 2009, Kondo  2003, Takahashi  2007, Wanat 2007). Bioinformatic algorithms suggest the variant is a uncertain significance, with the MAPP-MMR (multivariate analysis of protein polymorphism) score of 1.07, and class 2 by IARC (Chao 2008, Pastrello 2011).   The variant was also identified in the following databases: dbSNP (ID: rs41294980) “With other allele”, ClinVar (classifed benign, reviewed by an expert panel (2013); submitters: benign by InSIGHT, Invitae, GeneDx, Ambry Genetics, Mayo Clinic; uncertain significance by Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine) and Biesecker Lab/Human Development Section (NIH); likely benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics) and classification not provided by ITMI), UMD-LSDB (1x as neutral), Insight Colon Cancer Gene Variant Database (43x class 1), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (44x). The variant was not identified in the COGR, Cosmic, MutDB, and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 249 of 276804 chromosomes at a frequency of 0.0009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), and was identified in the following populations: African in 5 of 23990 chromosomes (frequency: 0002), Other in 14 of 6448 chromosomes (frequency: 002), Latino in 38 of 34410 chromosomes (frequency: 001), European Non-Finnish in 172 of 126420 chromosomes (frequency: 001), Ashkenazi Jewish in 8 of 10140 chromosomes (frequency: 00085), European Finnish in 2 of 25748 chromosomes (frequency: 00008), South Asian in 10 of 30782 chromosomes (frequency: 0003). The p.Ser406 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
True Health Diagnostics	RCV000130336	SCV000886683	likely benign	Hereditary cancer-predisposing syndrome	2018-07-13	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000121359	SCV001798938	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000121359	SCV001917779	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121359	SCV001955834	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000121359	SCV001974378	benign	not specified		no assertion criteria provided	clinical testing