Submissions for variant NM_000249.4(MLH1):c.1896+5G>A

gnomAD frequency: 0.00001  dbSNP: rs759870594

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575544	SCV000669548	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-21	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000764496	SCV000895567	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000575544	SCV000908648	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-09	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000998018	SCV001153850	uncertain significance	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV001041310	SCV001204916	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-18	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000998018	SCV003762048	uncertain significance	not provided	2023-01-26	criteria provided, single submitter	clinical testing	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)
All of Us Research Program, National Institutes of Health	RCV004001024	SCV004842066	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	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.