rs63751657
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000249.4(MLH1):c.1731G>A(p.Ser577=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MLH1
NM_000249.4 splice_region, synonymous
NM_000249.4 splice_region, synonymous
Scores
2
Splicing: ADA: 0.9900
2
Clinical Significance
Conservation
PhyloP100: 0.502
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 3-37042331-G-A is Pathogenic according to our data. Variant chr3-37042331-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 89857.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37042331-G-A is described in Lovd as [Pathogenic]. Variant chr3-37042331-G-A is described in Lovd as [Benign]. Variant chr3-37042331-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MLH1 | NM_000249.4 | c.1731G>A | p.Ser577= | splice_region_variant, synonymous_variant | 15/19 | ENST00000231790.8 | NP_000240.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MLH1 | ENST00000231790.8 | c.1731G>A | p.Ser577= | splice_region_variant, synonymous_variant | 15/19 | 1 | NM_000249.4 | ENSP00000231790 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1443524Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 719466
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
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1443524
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Cov.:
29
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0
AN XY:
719466
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
EpiCase
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EpiControl
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:17Uncertain:1Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 12, 2018 | The c.1731G>A (p.Ser577=) variant in the MLH1 gene has been reported in multiple unrelated patients with hereditary nonpolyposis colorectal cancer [PMID: 8808596, 16451135, 16341550, 21598002, 26300997]. This variant has not been observed in the general population according to the gnomAD database. This variant is next to the exon 15 splicing donor site and functional study showed that this variant causes exon 15 skipping [PMID:18561205]. Therefore, this c.1731G>A (p.Ser577=) variant in the MLH1 gene is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 06, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 15, 2023 | This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. Functional studies indicate this variant impacts protein function [PMID: 16341550]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [8808596, 16341550]. 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]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16341550, 15849733, 20223024, 18931482, 26300997, 14635101, 16216036). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16341550, 18561205, 16451135). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000089857). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:3Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 11, 2023 | The MLH1 c.1731G>A (p.Ser577=) synonymous variant has been reported in the published literature in individuals and families with Lynch syndrome (PMIDs: 26300997 (2015), 24278394 (2013), 20223024 (2006), 16395668 (2006)). This variant was shown to interfere with normal MLH1 mRNA splicing (PMIDs: 19669161 (2010), 18561205 (2008), 16341550 (2006)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2024 | Exonic splice site variant demonstrated to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease (PMID: 7704024, 8808596, 10596954, 11151427, 16341550); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18561205, 21598002, 16451135, 24278394, 19731080, 9087566, 10596954, 11112663, 18772310, 7704024, 21286823, 17576681, 8808596, 31830689, 28888541, 16395668, 19669161, 11151427, 14514376, 15046089, 16341550, 11601928, 18726168, 19072991, 21387278, 18931482, 26300997, 25345868, 15849733, 16216036, 20007843, 27064304, 28050887, 27601186, 22949379, 27007491, 26681312, 29706640, 29506128, 24456667, 14635101, 29887214, 30521064, 31054147, 20223024, 31447099, 32658311, 30787465, 35418818) - |
Lynch syndrome Pathogenic:2
| Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Variant causes splicing aberration leading to truncated protein: complete inactivation of variant allele - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | The p.Ser577Ser variant in MLH1 has been previously reported in at least 17 individuals with Lynch syndrome (Auclair 2006, Tournier 2008, Bozzao 2011, Kurzawski 2006, Kohonen-Corish 1996, Mangold 2005, Hinrichsen 2014, Betz 2010, Simbolo 2015, Pagenstecher 2006, De Lellis 2013) and was absent from large population studies. This variant was classified as Pathogenic by several clinical labs in ClinVar and on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89857). This variant is located in the last three bases of the exon, which is part of the 5’ splice region. Computational tools do not predict a splicing impact, though this information is not predictive enough to rule out pathogenicity. In vitro and in vivo functional studies support an impact on protein function, due to out-of-frame exon skipping (Auclair 2006, Tournier 2008, Kohonen-Corish 1996, Betz 2010, Pagenstecher 2006, De Lellis 2013). Heterozygous loss-of-function of the MLH1 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PS3, PS4, PM2. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 05, 2022 | The c.1731G>A pathogenic mutation (also known as p.S577S), located in coding exon 15 of the MLH1 gene, results from a G to A substitution at nucleotide position 1731. This nucleotide substitution does not change the serine at codon 577. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. This mutation has been reported in numerous individuals with HNPCC/Lynch syndrome or that have high suspicion for HNPCC/Lynch syndrome based on personal and/or family history (Pistorius SR et al. Int. J. Colorectal Dis. 2000 Nov;15(5-6):255-63; Mangold E et al. Int. J. Cancer. 2005 Sep;116(5):692-702; Pagenstecher C et al. Hum. Genet. 2006 Mar;119:9-22; Kurzawski G et al. Hered. Cancer Clin. Pract. 2006 Dec;4(4):197-205; Jasperson KW et al. Fam. Cancer, 2010 Jun;9:99-107; Bozzao C et al. Cancer. 2011 Sep;117(18):4325-35; De Lellis L et al. PLoS ONE. 2013 Nov;8(11):e81194; Simbolo M et al. Hered. Cancer Clin. Pract. 2015 Aug;13(1):18). This mutation has been shown in multiple RNA studies to result in skipping of coding exon 15, which is predicted to lead to a translational frameshift (Kohonen-Corish M et al. Am. J. Hum. Genet. 1996 Oct;59(4):818-24; Auclair J et al. Hum. Mutat. 2006 Feb;27(2):145-54; Pagenstecher C et.al. Hum. Genet. 2006 Mar;119:9-22; Tournier I et al. Hum. Mutat. 2008 Dec;29(12):1412-24; Ambry internal data). This nucleotide position is highly conserved through mammals. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as a pathogenic mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 07, 2021 | This variant alters the last nucleotide of exon 15 of the MLH1 gene. Functional studies using RNA derived from carrier individuals have shown that this variant causes a complete out-of-frame skipping of exon 15 and results in a premature protein truncation (PMID: 16341550, 16395668, 19669161). This variant has been reported in multiple individuals affected with Lynch syndrome (PMID: 8808596, 11151427, 14514376, 15849733, 16341550, 16451135, 20223024, 21598002, 24456667, 26300997, Insight-database.org). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 31, 2022 | - - |
Hereditary nonpolyposis colon cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 13, 2021 | Variant summary: MLH1 c.1731G>A (p.Ser577Ser) alters a non-conserved nucleotide that is located at the last nucleotide of exon 15, therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predicted a weak impact on normal splicing: 3/3 predict the variant slightly weakens a 5' donor site. However, multiple publications reported experimental evidence, demonstrating that this variant affects mRNA splicing, resulting in a complete skipping of exon 15, which is predicted to cause a frameshift at the protein level (Pagenstecher_2006, Auclair_2006, Tournier_2008, Betz_2010). The variant was absent in 251202 control chromosomes (gnomAD). The variant, c.1731G>A, has been reported in the literature in several individuals and families affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Kohonen-Corish_1996, Scott_2001, Raedle_2001, Pagenstecher_2006, Auclair_2006), and in numerous cases microsatellite instability and loss of the MLH1 protein was noted in the associated tumor. These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 08, 2021 | - - |
MLH1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 01, 2024 | The MLH1 c.1731G>A variant is not predicted to result in an amino acid change (p.=). This variant is present at the last nucleotide of exon 15 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. Based on available splicing prediction programs this variant is predicted to alter splicing (Alamut Visual v2.11). In addition, functional studies have shown that this variant results in the skipping of exon 15 (Kurzawski et al. 2006. PubMed ID: 16451135; Pagenstecher et al. 2006. PubMed ID: 16341550; Tournier et al. 2008. PubMed ID: 18561205). This variant has been reported in individuals with Lynch Syndrome, also known as hereditary non-polyposis colorectal cancer (Taylor et al. 2003. PubMed ID: 14635101; Mangold et al. 2005. PubMed ID: 15849733; Kurzawski et al. 2006. PubMed ID: 20223024; Pagenstecher et al. 2006. PubMed ID: 16341550; Sheng et al. 2008. PubMed ID: 18931482; Simbolo et al. 2015. PubMed ID: 26300997). To our knowledge, this variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89857/). This variant is interpreted as pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | This sequence change affects codon 577 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant 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 variant has been observed in individuals with Lynch syndrome (PMID: 14635101, 15849733, 16216036, 16341550, 18931482, 20223024, 21598002, 26300997). ClinVar contains an entry for this variant (Variation ID: 89857). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16341550, 16451135, 18561205). For these reasons, this variant has been classified as Pathogenic. - |
Colon cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 23, 2021 | Colon Cancer - |
Lynch syndrome 1 Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at