Submissions for variant NM_000249.4(MLH1):c.2103+6G>T

gnomAD frequency: 0.00001  dbSNP: rs1057521607

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000437903	SCV000523770	likely benign	not specified	2018-01-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550196	SCV000625126	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000582524	SCV000689864	likely benign	Hereditary cancer-predisposing syndrome	2017-06-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000582524	SCV002528716	likely benign	Hereditary cancer-predisposing syndrome	2021-11-13	criteria provided, single submitter	curation
Ambry Genetics	RCV000582524	SCV005134212	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-11	criteria provided, single submitter	clinical testing	The c.2103+6G>T intronic alteration consists of a G to T substitution nucleotides after coding exon 18 in the MLH1 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357276	SCV001552696	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MLH1 c.2103+6G>T variant was not identified in the literature nor was it identified in the dbSNP, GeneInsight-COGR, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database databases. The variant was identified in ClinVar (classified as likely benign by GeneDx, Color Genomics; as uncertain significance by Invitae), and Clinvitae databases. The variant was identified in control databases in 3 of 245256 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Finnish in 2 of 22292 chromosomes (freq: 0.0001), South Asian in 1 of 30754 chromosomes (freq: 0.00003), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, European, Latino, and Other populations. The c.2103+6G>T 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. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.