ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.277A>G (p.Ser93Gly) (rs41295282)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212516 SCV000149386 likely benign not specified 2017-10-25 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 RCV000115477 SCV000217328 likely benign Hereditary cancer-predisposing syndrome 2019-03-05 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification;Structural Evidence
Invitae RCV001085936 SCV000252648 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-26 criteria provided, single submitter clinical testing
Counsyl RCV000409754 SCV000487952 uncertain significance Lynch syndrome II 2015-12-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115477 SCV000910785 likely benign Hereditary cancer-predisposing syndrome 2015-01-19 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000524285 SCV001153833 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212516 SCV001362944 likely benign not specified 2019-02-04 criteria provided, single submitter clinical testing Variant summary: MLH1 c.277A>G (p.Ser93Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal and Histidine kinase/HSP90-like ATPase domains of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 277126 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.277A>G has been reported in the literature in affected individuals (Schneider_2018, Jansen_2016, Barnetson _2008, Hendriks _2003, Nystrom-Lahti_2002, Quaresima _1998). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Jansen_2016 reports a patient that carried the variant of interest along with another pathogenic germline MUTYH variant, c1187G>A (p.G396D) and a somatic MLH1 variant, c.281delT (p.(S95LfsX13), providing supporting evidence for a benign role. Several functional studies have been performed to assess the variant's impact on interaction and binding with PMS2 and Exo1, MMR activity, nuclear localization and expression, and splice pattern (Andersen_2012, Drost_2010, Takahashi_2007, Wanat_2007, Raevaara_2005, Nystrom-Lahti_2002, Ellison_2001). Thru these studies, the variant of interest was found to perform comparably to wild-type function. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (1x), likely benign (2x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000212516 SCV000691843 likely benign not specified no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000524285 SCV001550460 likely benign not provided no assertion criteria provided clinical testing The MLH1 p.Ser93Gly variant was identified in 16 of 2132 proband chromosomes (frequency: 0.007) from individuals or families with Lynch syndrome (Barnetson 2008, Jansen 2016, van Puijenbroek 2008, Raevaara 2005). The variant was also identified in dbSNP (ID: rs41295282 as "With Uncertain significance allele"), ClinVar (1x as benign by Invitae; 3x as likely benign by GeneDx, Ambry Genetics, and Mayo Clinic; and 2x as uncertain significance by InSiGHT and Counsyl), MutDB, UMD-LSDB (1x as unclassified variant), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors database (37x). The variant was not identified in the Gene Insight-COGR, Cosmic, or Zhejiang University databases. The variant was identified in control databases in 6 of 277126 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24028 chromosomes (freq: 0.00004), European in 4 of 126634 chromosomes (freq: 0.00003), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. In addition, several functional studies using in vitro Mismatch Repair Assays identify the variant has normal MMR activity (Andersen 2012, Drost 2010, Kansikas 2011, Ou 2007, Takahashi 2007, Thompson 2013, Wanat 2007, Raevaara 2005). However, the variant exhibited reduction of protein efficiency compared to the wild-type, suggesting this may be a low penetrance variant (Vogelsang 2009). The p.Ser93 residue is conserved in mammals but not in more distantly related organisms; however, 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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 addition, analysis using the pCAS reporter assay showed splice patterns of the variant allele were the same as the wild type (van der Klift 2015). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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