ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1217G>A (p.Ser406Asn) (rs41294980)

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Total submissions: 20
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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 2020-12-06 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: 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000121359 SCV000225492 likely benign not specified 2014-11-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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 Health, Inc 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,PreventionGenetics RCV000034539 SCV000805944 likely benign not provided 2017-04-06 criteria provided, single submitter clinical testing
Mendelics RCV000987170 SCV001136403 likely benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034539 SCV001153841 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000987170 SCV001307796 uncertain significance Lynch syndrome II 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.
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
Human Genetics - Radboudumc,Radboudumc RCV000121359 SCV001955834 benign not specified no assertion criteria provided clinical testing

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