ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.955G>A (p.Glu319Lys) (rs63750796)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656859 SCV000149398 uncertain significance not provided 2021-06-30 criteria provided, single submitter clinical testing Published functional studies demonstrate no damaging effect in a methylation tolerance assay (Bouvet 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20373145, 18566915, 26845104, 25871441, 27601186, 27498913, 28503720, 25186627, 30998989, 31391288, 31187078, 22753075)
Ambry Genetics RCV000115489 SCV000185511 likely benign Hereditary cancer-predisposing syndrome 2019-03-06 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);Other data supporting benign classification
Invitae RCV000524325 SCV000260533 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000075945 SCV000266184 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Counsyl RCV000410221 SCV000489392 uncertain significance Lynch syndrome II 2016-09-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212528 SCV000601418 uncertain significance not specified 2017-05-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115489 SCV000684885 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-13 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 319 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown the mutant protein to be functional in a methylation tolerance-based assay (PMID: 30998989). This variant has been reported in individuals affected with or suspected of having Lunch syndrome (PMID: 18566915, 20373145, 27601186), in individuals affected with breast cancer (PMID: 25186627, 26845104, 28503720) and in an individual affected with sarcoma (PMID: 27498913). This variant has been identified in 18/282792 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000764484 SCV000895555 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144597 SCV000189924 uncertain significance Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000656859 SCV000986701 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 11/29/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357697 SCV001553241 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MLH1 p.Glu319Lys variant was identified in 4 of 7680 proband chromosomes (frequency: 0.0005) from individuals or families with Lynch syndrome or breast cancer (Lagerstedt-Robinson 2016, Nilbert 2009, Shirts 2015, Tung 2015). The variant was also identified in dbSNP (ID: rs63750796) as "With Pathogenic, other allele", ClinVar (classified a likely benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx, Counsyl and five other submitters), and in UMD-LSDB (1x as unclassified variant).. The variant was identified in control databases in 17 of 277130 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24036 chromosomes (freq: 0.00004), Latino in 1 of 34420 chromosomes (freq: 0.00003), European in 15 of 126622 chromosomes (freq: 0.0001), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Glu319 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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