ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1013A>G (p.Asn338Ser) (rs63751467)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128912 SCV000172779 likely benign Hereditary cancer-predisposing syndrome 2019-02-04 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000524219 SCV000218987 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000656860 SCV000279079 uncertain significance not provided 2017-12-20 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1013A>G at the cDNA level, p.Asn338Ser (N338S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). MLH1 Asn338Ser has been observed in at least three individuals with colorectal cancer, two of which were diagnosed <40 years of age and one in which tumor testing reportedly exhibited microsatellite instability (MSI-H status) and loss of the MLH1 and PMS2 proteins via immunohistochemistry (Rossi 2002, Hardt 2011, Rodr?guez-Soler 2013). In addition, this variant was observed in an individual with breast cancer with a family history of breast and ovarian cancer, as well as in two cases of epithelial ovarian cancer (Pal 2012, Caminsky 2016). MLH1 Asn338Ser was shown, through the use of a yeast two-hybrid assay, to exhibit MLH1/PMS2 interaction similar to that of wild-type, suggesting that it does not impact binding with PMS2 (Wang 2012). MLH1 Asn338Ser was observed at an allele frequency of 0.01% (16/126,584) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. MLH1 Asn338Ser is located within the N-terminal ATPase domain (Andersen 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Asn338Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000220791 SCV000539649 uncertain significance not specified 2016-08-12 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: ClinVar: VUS by expert panel in 2013, no new evidence suggesting pathogenicity since then
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656860 SCV000601340 uncertain significance not provided 2020-07-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000128912 SCV000684708 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-16 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 338 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools and a RNA study suggest that this variant does not impact on RNA splicing (PMID: 18561205). To our knowledge, this variant has not been evaluated in experimental studies for its impact on protein function. This variant has been reported in multiple individuals affected with colorectal or other Lynch syndrome-associated cancers (PMID: 12095971, 18561205, 21404117, 23047549, 23354017) and two individuals with ovarian cancer (PMID: 23047549), and an individual with pancreatic ductal adenocarcinoma (PMID: 28767289). This variant has also been identified in 24/282676 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.
Mendelics RCV000075074 SCV000838006 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764485 SCV000895556 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000987162 SCV001136393 uncertain significance Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000220791 SCV001339155 uncertain significance not specified 2020-03-20 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1013A>G (p.Asn338Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 251274 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (9.2e-05 vs 0.00071), allowing no conclusion about variant significance. c.1013A>G has been reported in the literature in individuals affected with cancer including, Lynch syndrome, epithelial ovarian cancer, pancreatic ductal adenocarcinoma and breast cancer (e.g. Caminsky_2016, Hardt_2011, Koger_2018, Pal_2012, Shindo_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In functional studies the variant was found to have no effect on RNA splicing, protein expression or mismatch repair activity (e.g. Koger_2018, Tournier_2008). Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=8) and as likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656860 SCV001500304 likely benign not provided 2020-08-01 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148621 SCV000190336 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356843 SCV001552114 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MLH1 p.Asn338Ser variant was identified in 5 of 7614 proband chromosomes (frequency: 0.001) from individuals or families with colon, and ovarian cancer (Chao 2008, Hardt 2011, Pal 2012, Rodriguez-Soler 2013). The variant was also identified in the following databases: dbSNP (ID: rs63751467) as “With Uncertain significance allele”, in ClinVar (classified as likely benign by Ambry Genetics; classified as uncertain significance by Invitae, GeneDx, Color Genomics and 4 clinical laboratories), Clinvitae, UMD-LSDB (5X as unclassified variant), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (15X Class3). The variant was not identified in COGR, Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 23 of 277060 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24032 chromosomes (freq: 0.00004), Latino in 2 of 34418 chromosomes (freq: 0.0001), European in 16 of 126584 chromosomes (freq: 0.0001), Finnish in 2 of 25792 chromosomes (freq: 0.0001), and South Asian in 2 of 30780 chromosomes (freq: 0.0001); it was not observed in the “Other”, Ashkenazi Jewish, or East Asian populations. Several publications provide inconsistent predictions regarding the effect of the variant on protein and splicing. The variant was shown to have a deleterious effect with an in silico model (Chao 2008), while the variant has no effect on splicing in the pCAS ExVivo Splicing Assay (Tournier 2008). The p.Asn338 residue is conserved in mammals but not in more distantly related 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 4 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, 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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