ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.649C>T (p.Arg217Cys) (rs4986984)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590255 SCV000149392 likely benign not provided 2020-12-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 8581513, 11555625, 17594722, 21901500, 11920458, 27487738, 29752822, 32601921, 23760103, 11781295, 20176959, 17510385, 22949387, 12810663, 27553368, 18094436, 8797773, 9559627, 15613555, 16425354, 22136435, 17074586, 27173243, 28452373, 28389907, 29505604, 28767289, 31010795, 30740464, 30521064, 30850667, 31386297, 31784484)
Invitae RCV001079587 SCV000166256 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115483 SCV000184755 likely benign Hereditary cancer-predisposing syndrome 2018-09-24 criteria provided, single submitter clinical testing Other data supporting benign classification
Color Health, Inc RCV000115483 SCV000689902 benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212524 SCV000696175 likely benign not specified 2020-09-25 criteria provided, single submitter clinical testing Variant summary: MLH1 c.649C>T (p.Arg217Cys) results in a non-conservative amino acid change located in the N-terminal domain that functions in promoting dimerization (IPR002099). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 252977 control chromosomes, predominantly at a frequency of 0.0047 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.649C>T has also been reported in the literature in several individuals affected with Lynch Syndrome, who were predominantly of Asian descent and the majority of these publications only performed evaluation of MLH1 and could not rule out variants in other Lynch syndrome associated genes. These reports therefore do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In addition, in one publication (Sapari 2014), the variant was found in co-occurrence with another pathogenic MLH1 variant, c.790+1G>A (although it was only identified through NGS and not confirmed by Sanger sequencing). One co-occurrence with another pathogenic variant has been reported internally (BRCA2 c.1648G>T , p.Glu550X), providing supporting evidence for a benign role. Several publications reported experimental evidence evaluating an impact on protein function (Ellison 2001, Trojan 2002, Kondo 2003, Takahashi 2007, Zhao 2008, Peng 2016), showing no or only a mild effect on function. A recent study suggested based on in vitro evidence that the variant might affect splicing by affecting splicesome assembly (Rhine 2018), however earlier reports that identified the variant in patients through RNA-based direct sequencing, did not indicate any specific splicing effect (Furukawa 2002, Wang 2005); therefore, the significance of this finding is uncertain. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (4x), likely benign (3x) and benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000075793 SCV000838001 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590255 SCV000889402 likely benign not provided 2019-10-22 criteria provided, single submitter clinical testing
Mendelics RCV000987154 SCV001136381 uncertain significance Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030563 SCV001193607 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000987154 SCV001305703 uncertain significance Lynch syndrome II 2017-05-04 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590255 SCV001500302 uncertain significance not provided 2020-12-01 criteria provided, single submitter clinical testing
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093666 SCV001250847 uncertain significance Lynch syndrome I no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354844 SCV001549555 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MLH1 p.Arg217Cys variant was identified in 12 of 656 proband chromosomes (frequency: 0.02) from individuals or families with Extramammary Paget disease or sporadic colorectal cancer and was present in 8 of 1260 control chromosomes (frequency: 0.006) from healthy individuals (Kang 2016, Peng 2015). The variant was also identified in dbSNP (ID: rs4986984) as "With other allele”, ClinVar (classified as benign by Color; as likely benign by Invitae, GeneDx, Ambry Genetics and one clinical laboratory; as uncertain significance by two clinical laboratories), Cosmic (4x in Skin or bone tissue), MutDB , UMD-LSDB (2x as neutral), Zhejiang University Database, Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors (42x as uncertain) databases. The variant was not identified in COGR database. The variant was identified in control databases in 91 of 276864 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 126374 chromosomes (freq: 0.00002), East Asian in 83 of 18868 chromosomes (freq: 0.004), and South Asian in 6 of 30782 chromosomes (freq: 0.0002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, and Finnish, populations. The p.Arg217 residue is conserved in mammals but not in more distantly related organisms, and 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. Several functional studies identified the variant might affect the MMR process at different levels and might have functional relation to gastrointestinal cancer. The variant showed variable levels of MMR activity (50%, 64.8%, or 81.3%) compare to WT however overall the studies concluded that although efficiency of MMR is slightly reduced it is still proficient (Kang 2016, Lucci-Cordisco 2006, Fan 2007, Takahashi 2007, Trojan 2002). 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000590255 SCV001808355 likely benign not provided no assertion criteria provided clinical testing

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