Submissions for variant NM_000249.4(MLH1):c.1558+5G>A

gnomAD frequency: 0.00008  dbSNP: rs199935667

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590226	SCV000149370	uncertain significance	not provided	2023-06-07	criteria provided, single submitter	clinical testing	Observed in a family fulfilling Amsterdam criteria II for Lynch syndrome (Tang et al., 2009); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 26332594, 30093976, 29887214, 26053027, 32363481, 19419416, 10861474)
Ambry Genetics	RCV000115461	SCV000218331	likely benign	Hereditary cancer-predisposing syndrome	2020-04-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086042	SCV000259283	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515436	SCV000611398	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115461	SCV000684754	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 13 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with ovarian cancer (PMID: 30093976) and gastric cancer (PMID: 10861474), as well as in a family that met Amsterdam criteria II for Lynch syndrome (PMID: 19419416). This variant also has been identified in 36/282692 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175375	SCV000696115	uncertain significance	not specified	2019-10-21	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1558+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict that the variant weakens a 5' donor site. Two predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 251300 control chromosomes, predominantly at a frequency of 0.0013 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2-fold over the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.1558+5G>A, has been reported in the literature in individuals affected with Lynch Syndrome (Tang 2009, Kamiza 2015) and other tumor phenotypes (Bevilacqua 2000, Chan 2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other ClinVar submissions (evaluation after 2014) cite the variant five times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Counsyl	RCV000663109	SCV000786227	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-03-23	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758646	SCV000887407	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.1558+5G>A has a 59.6% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
CeGaT Center for Human Genetics Tuebingen	RCV000590226	SCV001748064	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149796	SCV003838212	uncertain significance	Breast and/or ovarian cancer	2022-05-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663109	SCV004018145	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	criteria provided, single submitter	clinical testing	This variant is considered 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]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001175375	SCV004024909	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590226	SCV004220077	uncertain significance	not provided	2022-05-19	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0012 (24/19952 chromosomes in East Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in a Taiwanese family with Lynch syndrome (PMID: 19419416 (2009)), as well as in an individual with ovarian cancer (PMID: 30093976 (2018)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper MLH1 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000663109	SCV005402187	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-03-11	criteria provided, single submitter	clinical testing	The MLH1 c.1558+5G>A intronic change results in a G to A substitution at the +5 position of intron 13 of the MLH1 gene. Algorithms that predict the impact of sequence changes on splicing indicate that this change may impact splicing, and internal RNA data cannot conclusively determine the impact of this variant. This variant has a maximum subpopulation frequency of 0.12% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been reported in a family that met Amsterdam II criteria (PMID: 19419416). To our knowledge, this variant has not been reported in individuals with constitutional mismatch repair deficiency syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.