ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.375A>G (p.Ala125=) (rs1800144)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075671 SCV000106673 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Synonymous substitution with no effect on splicing, tested with NMD inhibitor
GeneDx RCV000212518 SCV000170286 benign not specified 2013-11-05 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 RCV000126771 SCV000212822 likely benign Hereditary cancer-predisposing syndrome 2014-08-05 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Invitae RCV001083128 SCV000252649 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000412240 SCV000487814 likely benign Lynch syndrome II 2015-11-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212518 SCV000601396 likely benign not specified 2017-04-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000126771 SCV000684823 benign Hereditary cancer-predisposing syndrome 2015-04-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656541 SCV000805969 likely benign not provided 2017-03-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000656541 SCV000884120 benign not provided 2018-06-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656541 SCV000888185 benign not provided 2018-05-15 criteria provided, single submitter clinical testing
Mendelics RCV000412240 SCV001136374 likely benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656541 SCV001153834 likely benign not provided 2017-02-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000412240 SCV001310311 likely benign Lynch syndrome II 2017-10-17 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000656541 SCV000691847 benign not provided 2017-11-30 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355849 SCV001550854 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The MLH1 p.Ala125= variant was identified in dbSNP (ID: rs1800144 as With Likely benign allele), ClinVar (likely benign as reviewed by expert panel; 8x as benign or likely benign), Cosmic (1x), UMD-LSDB (9x, classified as neutral, co-occurred with pathogenic variants in MLH1 or MSH2 3x), Insight Colon Cancer Gene Variant Database (6x, as likely not pathogenic), and Mismatch Repair Genes Variant Database. The variant was also identified in control databases in 150 of 277158 chromosomes at a frequency of 0.0005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was identified in the following populations: African in 4 of 24038 chromosomes (freq: 0.0002), Other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 77 of 34418 chromosomes (freq: 0.002237), European Non-Finnish in 65 of 126642 chromosomes (freq: 0.0005), and Ashkenazi Jewish in 1 of 10150 chromosomes (freq: 0.0001); it was not observed in the East Asian, Finnish, or South Asian populations. The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The p.Ala125= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, one study using RT-PCR from patient RNA followed by sequencing did not detect aberrant splicing (Auclair 2006). In summary, the clinical significance of this variant cannot be determined with certainty at this time although the available information is suggestive of a benign role. This variant is classified as likely benign.

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