Submissions for variant NM_000249.4(MLH1):c.794G>A (p.Arg265His)

gnomAD frequency: 0.00004  dbSNP: rs63751448

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524318	SCV000166257	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 265 of the MLH1 protein (p.Arg265His). This variant is present in population databases (rs63751448, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 8993976, 18561205; Invitae). ClinVar contains an entry for this variant (Variation ID: 90381). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 9697702, 11781295, 12810663, 17510385, 23403630). Studies have shown this missense change is associated with skipping of exon 10 and/or skipping of exons 10-11, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 30623411, 31332305, 32133419; Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000131125	SCV000186056	likely benign	Hereditary cancer-predisposing syndrome	2020-05-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000656858	SCV000211097	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	Published functional studies are conflicting: normal protein expression, but also partial exon skipping and inconsistent mismatch repair function (Shimodaira et al., 1998; Ellison et al., 2001; Kondo et al., 2003; Takahashi et al., 2007; Tournier et al., 2008; Hinrichsen et al., 2013; Soukarieh et al., 2016); Observed in individuals with MLH1-related cancers, occurring on the same allele (in cis) with a truncating MLH1 variant in one family (Viel et al., 1997; Tournier et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22736432, 20176959, 23403630, 25525159, 28492532, 10573010, 31697235, 21239990, 12810663, 17510385, 11781295, 17210669, 17594722, 9697702, 25871441, 18205192, 16830052, 17192056, 23741719, 18373977, 26761715, 11555625, 18561205, 8993976, 9827806, 28668638, 29520894, 19339519, 22290698, 32170000, 33326660, 35731023, 22753075, 31332305, 30623411, 32133419, 18383312, 37240284)
Counsyl	RCV000410210	SCV000487858	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2015-11-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212526	SCV000539646	uncertain significance	not specified	2016-06-16	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: 13 papers in HGMD, however several of these call pathogenicity into question. ClinVar: 3 VUS (including expert panel - no new evidence since this classification), 1 LB
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000212526	SCV000592380	uncertain significance	not specified	2014-12-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131125	SCV000910975	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212526	SCV000919666	likely benign	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.794G>A (p.Arg265His) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain of the encoded protein sequence. 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 4.8e-05 in 251462 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (4.8e-05 vs 0.00071), allowing no conclusion about variant significance. c.794G>A has been reported in the literature in individuals affected with Lynch Syndrome (example, Pastrello_2011, Tournier_2008). Two families reported in Pastrello_2011, identified the variant to co-occur with a pathogenic MLH1 variant, c.1011delC (p.Asn338fs). In addition, one of the families showed the variant of interest to lack cosegregation with disease. Tournier_2008 also reports the variant to co-occur with another pathogenic MLH1 variant, c.1989G>T (p.Glu663Asp). The reported co-occurrences with other pathogenic variant(s) (MLH1 c.1989G>T, p.Glu663Asp; MLH1 c.1011delC, p.Asn338fs) and the lack of segregation with disease, provide supporting evidence for a benign role. Several publications reporting experimental evidence with conflicting interpretations with some showing no impact of the variant on protein function and mismatch repair (MMR) activity, while others do report reduced MMR efficiency (Hinrichsen_2013, Borras_2012, Martinez_2010, Zhao_2008, Takahashi_2007, Wanat_2007, Kondo_2003, Trojan_2002, Ellison_2001, Shimodaira_1998). Furthermore, conflicting experimental evidence was observed in regards to RNA splicing with indications of varying levels of exon 10 skipping to no effect (Soukarieh_2016, Borras_2012, Pastrello_2011, Tournier_2008). The following publications have been ascertained in the context of this evaluation (PMID: 22736432, 18383312, 11555625, 10573010, 23403630, 12810663, 28492532, 21239990, 9697702, 26761715, 17510385, 18561205, 11781295, 8993976, 17210669, 26580448, 18373977). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Some submitters cite overlapping evidence utilized in the context of this evaluation and at-least one submitter has re-classified this variant as likely benign since our previous evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656858	SCV001134324	uncertain significance	not provided	2018-12-21	criteria provided, single submitter	clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV001253793	SCV001429664	uncertain significance	Hereditary nonpolyposis colon cancer	2019-03-12	criteria provided, single submitter	clinical testing	Data included in classification: Predicted deleterious on SIFT, Polyphen, Align GVGD; Polyphen HumVar (PP3_sup). Three other variants at this position p.(Arg265Ser) and p.(Arg265Pro) and p.(Arg265Cys) all classed as likely pathogenic/pathogenic by InSiGHT. All of these have sufficient additional evidence (RNA studies / segregation / multiple cases / MSI / IHC) to support the classifications (PM5_mod). Additional information (not included in classification): 2 UK families. UK Family 1: Proband: Breast cancer at 42, Mucinous ovarian cancer. IHC: normal. Mother: Colorectal cancer at 74. IHC: normal. UK Family 2: Proband: Right sided bowel cancer age 51, Loss of MSH6 and MSH2 on IHC and MSI-High. Proband also had pathogenic MSH2. Literature (as per INSIGHT): 2 Italian families: In both variant is in cis with frameshift variant (Viel et al 1997, Genuardi et al 1999, Pastrello et al, 2011). 1 French family: Variant in trans with pathogenic MLH1 variant (Tournier et al 2008). Controls: The variant was observed 8/56,871 GNOMAD NFE controls and 4/68,860 individuals in the remainder of the GNOMAD population. Splicing data: Splicing predictions equivocal. Splicing functional data conflicting: (some functional affect on splicing: PMID 17510385, 18561205, 25525159, no effect/minimal effect PMID 9697702, 12810663, 23403630). Other classifications: Multiple classifications of VUS in ClinVar.
Molecular Oncology Research Center, Barretos Cancer Hospital	RCV001374504	SCV001438597	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000656858	SCV002062445	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410210	SCV004018132	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212526	SCV004024899	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131125	SCV004228002	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-06	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000131125	SCV000788026	uncertain significance	Hereditary cancer-predisposing syndrome	2017-11-01	no assertion criteria provided	clinical testing