Submissions for variant NM_000249.4(MLH1):c.1667+4A>G

dbSNP: rs983986337

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464057	SCV000543585	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777682	SCV000913613	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-26	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the +4 position of intron 14 of the MLH1 gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in an individual affected with early-onset colorectal cancer (communications with an external laboratory). This variant has not been identified 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	RCV000777682	SCV001173103	likely benign	Hereditary cancer-predisposing syndrome	2019-11-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001354080	SCV002072788	uncertain significance	not provided	2022-01-28	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; Has not been previously published as pathogenic or benign to our knowledge
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002254696	SCV002526015	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2022-03-22	criteria provided, single submitter	clinical testing	The MLH1 c.1667+4A>G intronic change results in a A to G substitution at the +4 position of intron 14 of the MLH1 gene. Algorithms that predict the impact of sequence changes on splicing indicate that this change may result in loss of the native donor at c.1667 (PP3), and internal RNA data cannot conclusively determine the impact of this variant. This variant is absent in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3.
Baylor Genetics	RCV002254696	SCV004195104	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-02-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000655	SCV004835523	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the +4 position of intron 14 of the MLH1 gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in an individual affected with early-onset colorectal cancer (communications with an external laboratory). This variant has not been identified 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.
Fulgent Genetics, Fulgent Genetics	RCV005033966	SCV005662520	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2024-01-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002254696	SCV005895116	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2024-11-25	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354080	SCV001548608	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MLH1 c.1667+4A>G variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs983986337) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae and Color). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1667+4A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Further, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.