Submissions for variant NM_000249.4(MLH1):c.678-4A>G

gnomAD frequency: 0.00001  dbSNP: rs766711342

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000220973	SCV000279462	uncertain significance	not provided	2023-08-27	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; Observed in an individual with pancreatic cancer (Paduano et al., 2022); This variant is associated with the following publications: (PMID: 35886069)
Invitae	RCV000458929	SCV000543602	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-08	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. This variant is present in population databases (rs766711342, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 234545). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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.
Color Diagnostics, LLC DBA Color Health	RCV000579799	SCV000684858	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -4 position of intron 8 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with pancreatic cancer (PMID: 35886069). This variant has been identified in 3/250318 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.
Ambry Genetics	RCV000579799	SCV001187875	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-10	criteria provided, single submitter	clinical testing	The c.678-4A>G intronic variant results from an A to G substitution 4 nucleotides upstream from coding exon 9 in the MLH1 gene. This nucleotide position is highly conserved in available vertebrate species. This variant was detected in 1/104 cases of familial cancer patients in an Italian cohort (Paduano F et al. Genes (Basel), 2022 Jul;13). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated this alteration results in the in-frame insertion of one amino acid; however, the exact functional impact of this inserted amino acid is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003469109	SCV004190619	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-09-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998625	SCV004825414	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -4 position of intron 8 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with pancreatic cancer (PMID: 35886069). This variant has been identified in 3/250318 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.