ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1667+1G>A (rs1434898623)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000536108 SCV000625089 pathogenic Hereditary nonpolyposis colorectal neoplasms 2017-12-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been reported in the literature in an individual affected with Lynch syndrome (PMID: 26248088). A different variant affecting this nucleotide (c.1667+1G>T) has been determined to be pathogenic in a family affected with Lynch syndrome (PMID: 21642682). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000563359 SCV000669523 pathogenic Hereditary cancer-predisposing syndrome 2017-06-19 criteria provided, single submitter clinical testing The c.1667+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the MLH1 gene. This alteration was detected in an individual with colon and small bowel cancer from a family who meets Amsterdam II criteria (Guindalini RS et al. Gastroenterology 2015 Nov; 149(6):1446-53). Another substitution at this same nucleotide position (c.1667+1G>T) has been reported in a family with Lynch syndrome (Bonadona V et al. JAMA 2011;305(22):2304-10). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Color Health, Inc RCV000563359 SCV001346687 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-21 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677882 SCV000804043 pathogenic Malignant tumor of colon 2017-11-02 no assertion criteria provided clinical testing

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