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.Ser577Ser) 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
Consequence
NM_000249.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
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 genome
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:4
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]. -
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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. -
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
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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) -
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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. -
Lynch syndrome Pathogenic:2
Variant causes splicing aberration leading to truncated protein: complete inactivation of variant allele -
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
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. -
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. -
Breast and/or ovarian cancer Pathogenic:1
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Hereditary nonpolyposis colon cancer Pathogenic:1
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
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MLH1-related disorder Pathogenic:1
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
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 altered 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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. 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
Colon Cancer -
Lynch syndrome 1 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at