Submissions for variant NM_000249.4(MLH1):c.793C>T (p.Arg265Cys)

dbSNP: rs63751194

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075872	SCV000106886	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes aberrant splicing leading to truncated protein: full inactivation of variant allele.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524317	SCV000262499	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 265 of the MLH1 protein (p.Arg265Cys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer or Lynch syndrome (PMID: 12386821, 15713769, 19419416, 20587412, 20864636). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29654). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 11555625, 11781295, 17135187, 17510385). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18561205, 22736432, 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000220712	SCV000276047	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-01	criteria provided, single submitter	clinical testing	The p.R265C pathogenic mutation (also known as c.793C>T), located in coding exon 10 of the MLH1 gene, results from a C to T substitution at nucleotide position 793. The arginine at codon 265 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been identified in many individuals with early-onset colorectal cancer with concordant tumor results and family histories which meet Amsterdam criteria (Trojan J et al. Gastroenterology. 2002 Jan;122:211-9; Wolf B et al. Wien. Klin. Wochenschr. 2005 Apr;117:269-77; Woods MO et al. Gut. 2010 Oct;59:1369-77; Hardt K et al. Fam. Cancer. 2011 Jun;10:273-84; Ambry internal data). This mutation has been associated with exon-skipping, premature protein truncation, and low expression of the variant allele (Casey G et al. JAMA. 2005 Feb;293:799-809; Tournier I et al. Hum. Mut. 2008 Dec;29:1412-24; van der Klift HM et al. Mol. Genet. Genomic Med. 2015 Jul;3:327-45). This mutation has also been shown to segregate with disease in several families meeting Amsterdam criteria (De Jong AE et al. Gastroenterology. 2004 Jan;126:42-8; Tang R et al. Clin. Genet. 2009 Apr;75:334-45; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000034802	SCV000279078	pathogenic	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: aberrant splicing and reduced mRNA and protein expression as well as deceased protein stability and reduced binding of MLH1 to PMS2 (Yuen et al., 2002; Casey et al., 2005; Perera et al., 2008; Perera et al., 2010; Andersen et al., 2012; Fan et al., 2012; Soukarieh et al., 2016); Observed in individuals with personal or family histories consistent with pathogenic variants in MLH1 and concordant tumor studies (Wahlberg et al., 1999; Hutter et al., 2002; Yuen et al., 2002; Hendriks et al., 2003; Mangold et al., 2005; Wolf et al., 2005; Lagerstedt Robinson et al., 2007; Berginc et al., 2009; Choi et al., 2009; Tang et al., 2009; Chang et al., 2010; Sjursen et al., 2010; Woods et al., 2010; Bonadona et al., 2011; Hardt et al., 2011; Fan et al., 2012; Liu et al., 2014; Guindalini et al., 2015; Win et al., 2015; Jiang W et al., 2019; Chang et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17210669, 20020535, 18561205, 22824075, 20045164, 21404117, 20682701, 19224586, 21681552, 20864636, 28127413, 15731775, 21952876, 11781295, 11555625, 17594722, 22736432, 22949387, 22753075, 17135187, 23760103, 10495924, 16995940, 15849733, 12547705, 19698169, 26247049, 22843852, 24710284, 21642682, 16216036, 19526325, 20587412, 25345868, 17312306, 21155023, 26053027, 26248088, 17192056, 15926618, 12011148, 26202870, 23741719, 16830052, 15713769, 12386821, 17510385, 26761715, 25081409, 11948175, 28445943, 30274973, 31589614, 32849802, 31332305, 19419416, 18205192, 33260537, 29758216, 24362816, 31447099, 30787465, 30521064, 31830689)
Counsyl	RCV000022502	SCV000677736	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2017-03-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220712	SCV000684870	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 265 in the MutS interacting domain 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). Functional studies have shown that this variant significantly decreases MLH1 protein stability (PMID: 18205192) and the ability of MLH1 protein to bind PMS2 (PMID: 21952876). This variant has also been shown to affect mRNA splicing (PMID: 12386821, 15713769, 18561205). This variant has been reported in individuals affected with Lynch syndrome or colorectal cancer (PMID: 12386821, 15713769, 19419416, 20587412, 20864636). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075872	SCV000696181	pathogenic	Lynch syndrome	2016-04-21	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Cysteine (C). 4/4 in silico tools predict the variant to be disease causing (SNPs&GO was not capture due to low reliability index). The variant is absent from the large and broad cohorts of the ExAC project while it was observed in several HNPCC patients indicating pathogenicity. Moreover, the variant is considered to be a founder mutation in populations of Chinese/Taiwanese origin. Functional studies report the variant to result in exon skipping and a partial MMR defect which in combination likely result in a pathogenic impact. Furthermore, a clinical laboratory and databases cite variant as Pathogenic. Considering all evidence, the variant was classified as a Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000075872	SCV000731294	pathogenic	Lynch syndrome	2016-11-17	criteria provided, single submitter	clinical testing	The p.Arg265Cys variant in MLH1 is absent from large population studies but has been reported in >30 individuals with Lynch Syndrome (Casey 2005, Hardt 2011, Ta ng 2009, InSiGHT database: http://chromium.lovd.nl/LOVD2/colon_cancer/variants.p hp). It segregated with disease in at least 12 family members (Hardt 2011, Tang 2009). Functional studies using patient mRNA showed that the variant leads to ex on skipping and protein truncation (Casey 2005). Additionally, this variant has been classified as pathogenic on Sept 5, 2013 by the ClinGen-approved InSiGHT pa nel (ClinVar SCV000106886.2). In summary, this variant meets criteria to be clas sified as pathogenic for Lynch Syndrome in an autosomal dominant manner based up on segregation studies and the impact of the variant on the protein.
3DMed Clinical Laboratory Inc	RCV000677879	SCV000804040	pathogenic	Carcinoma of colon	2018-02-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000022502	SCV001429381	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-06	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000034802	SCV001449582	pathogenic	not provided	2014-09-22	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034802	SCV002009353	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000022502	SCV004018207	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. This variant is expected to disrupt protein structure [Myriad internal data].
Neuberg Centre For Genomic Medicine, NCGM	RCV000022502	SCV004176523	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.793C>T(p.Arg265Cys) variant in MLH1 gene has been reported in heterozygous state in multiple individuals affected with colorectal cancer (Tang R, et. al., 2009; Choi YH, et. al., 2009). This variant has been observed to segregate with disease (Tang R, et. al., 2009). Functional studies demonstrate skipping of exon 9-10, aberrant splicing, reduced mRNA and protein expression as well as deceased protein stability, hence proving a damaging effect (Fan Y, et. al., 2012; Casey G, et. al., 2005). The p.Arg265Cys variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic (multiple submissions). The amino acid change p.Arg265Cys in MLH1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 265 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000022502	SCV004190609	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-11-19	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034802	SCV000043333	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
OMIM	RCV000022502	SCV000043791	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2009-04-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000677879	SCV000592378	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Arg265Cys variant has been previously reported in the literature and by our laboratory. It is also reported in dbSNP from a clinical source (dbSNP#:rs63751194). In one study, this variant was reported in 2 different families and was associated with skipping of exons 9 and 10 from cDNA (Casey 2005). In another report, including probands who met Amsterdam criteria for HNPCC or who had a family history, this variant was found to reduce exon inclusion. This variant has been tested in different functional assays at the protein level, with results that were not always consistent; the p.Arg265Cys was associated with a mild reduction of mismatch repair efficiency in four studies (Plotz 2006; Ellison 2001; Wanat 2007; Takahashi 2007) but not in a fifth one (Trojan 2002) (Tournier 2007). One large study of Tawainese patients demonstrated that the p.Arg265Cys variant was identified in 13 out of 93 unrelated families. In total, 93 cancers were noted in these 13 families including 66 with cases of colon cancer, 6 cases of rectal cancer, 3 cases of endometrial cancer, 6 cases of gastric cancer, 1 case of ovarian cancer and 11 cases of other types of cancer (Tang 2009). In another report, deficient MLH1 IHC status and MSI-H tumor was noted in an individual with this variant who developed colorectal cancer at age 55 (Perera 2010). In summary, based on the above information this variant is classified as pathogenic.
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093673	SCV001250854	pathogenic	Lynch syndrome 1		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034802	SCV001959956	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000034802	SCV001964907	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV001093673	SCV002054063	not provided	Lynch syndrome 1		no assertion provided	literature only