Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000231790.8(MLH1):c.1896+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,706 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).
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]
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Jan 26, 2023
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Published functional studies demonstrate that this variant is suspected to affect splicing (Chen et al., 2019); Observed in an individual with lung and gastric cancer (Chen et al., 2019); This variant is associated with the following publications: (PMID: 33933134, 31207149) -
Uncertain significance, criteria provided, single submitter
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 21, 2023
The c.1896+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 16 in the MLH1 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Nov 09, 2023
This variant causes a G to A nucleotide substitution at the +5 position of intron 16 of the MLH1 gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. This variant has been reported in an individual affected with gastric and lung cancer and suspected of Lynch syndrome (PMID: 31207149). This variant has also been identified in 3/251376 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. -
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Baylor Genetics
Feb 20, 2024
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Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Fulgent Genetics, Fulgent Genetics
Oct 31, 2018
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Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Dec 13, 2023
This variant causes a G to A nucleotide substitution at the +5 position of intron 16 of the MLH1 gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. This variant has been reported in an individual affected with gastric and lung cancer and suspected of Lynch syndrome (PMID: 31207149). This variant has also been identified in 3/251376 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. -
Uncertain significance, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Oct 18, 2023
This sequence change falls in intron 16 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs759870594, gnomAD 0.006%). This variant has been observed in individual(s) with gastric and lung cancer (PMID: 31207149). ClinVar contains an entry for this variant (Variation ID: 483545). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -