3-37049020-A-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000249.4(MLH1):c.2103+3A>G variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000249.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2
This variant is considered likely 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. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 32133419, 31641931, 38311346]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21642682; Myriad internal data]. -
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Hereditary cancer-predisposing syndrome Pathogenic:2
The c.2103+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 18 in the MLH1 gene. This alteration was identified in individuals with a family history that met Amsterdam I criteria for Lynch syndrome and/or showed loss of MLH1 and PMS2 protein expression by immunohistochemistry in their colorectal tumors (Ambry internal data). This alteration was also identified in a French family suspected of having Lynch syndrome; however, the clinical phenotype and tumor characteristics were not provided (Bonadona, V et al. JAMA. 2011 Jun 8;305(22):2304-10). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
This variant causes an A>G nucleotide substitution at the +3 position of intron 18 of the MLH1 RNA. Computational splicing tools predict that this variant may have a significant impact on RNA splicing. The Universal Mutation Database (UMD) reported the skipping of exon 18 as detected in the RT-PCR analysis of carrier RNA (http://www.umd.be/MLH1/4DACTION/Web_D_splice/53). This variant has been reported in a French family suspected of having Lynch syndrome (PMID: 21642682) and in individuals with a family history that met Amsterdam I criteria for Lynch syndrome and/or showed loss of MLH1 and PMS2 protein expression by immunohistochemistry in their colorectal tumors (ClinVar SCV000276974.5, communication with external laboratory). 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 Likely Pathogenic. -
not provided Pathogenic:1
The MLH1 c.2103+3A>G variant has been reported in the published literature in an individual with Lynch Syndrome (PMID: 21642682 (2011)). This variant was also determined to result in aberrant MLH1 splicing (PMID: 31642931 (2019)). In addition, internal laboratory data indicates that this variant was observed in an individual with colorectal cancer. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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, this variant is classified as likely pathogenic. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change falls in intron 18 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Lynch syndrome (external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 90047). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 18, but is expected to preserve the integrity of the reading-frame (internal data). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at