ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1731+5G>A

dbSNP: rs267607850
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075328 SCV000106321 pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Variant causes splicing aberration leading to truncated protein: complete inactivation of variant allele
Invitae RCV001201385 SCV000261840 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-14 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 18561205, 19685281). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18561205, 19685281, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 15 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein, but it affects a nucleotide within the consensus splice site of the intron.
Ambry Genetics RCV001012888 SCV001173402 pathogenic Hereditary cancer-predisposing syndrome 2020-09-11 criteria provided, single submitter clinical testing The c.1731+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 15 in the MLH1 gene. This alteration has been reported in an individual with colorectal cancer whose family history met Amsterdam criteria for Lynch syndrome (Naruse H et al. Fam. Cancer 2009 Aug;8(4):509-17). This alteration has also been identified in an individual whose uterine tumor displayed loss of both MLH1/PMS2 staining on immunohistochemistry (IHC) with absent MLH1 promoter hypermethylation and had a family history of Lynch syndrome-associated cancers (Ambry internal data). Furthermore, RNA functional studies demonstrated exon 15 skipping for this variant resulting in a truncated transcript subject to nonsense mediated decay (Tournier I et al. Hum. Mutat. 2008 Dec;29(12):1412-24; Naruse H et al. Fam. Cancer 2009 Aug;8(4):509-17). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV002279946 SCV002568790 likely pathogenic not provided 2022-02-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19685281, 18561205)
Myriad Genetics, Inc. RCV003451056 SCV004186368 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-21 criteria provided, single submitter clinical testing This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 16341550].

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