ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.380+1G>A (rs267607745)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075679 SCV000106682 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV000524296 SCV000284061 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-03-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the MLH1 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with suspected Lynch syndrome (PMID: 15849733, 19072991). ClinVar contains an entry for this variant (Variation ID: 90191). In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.
GeneDx RCV000486012 SCV000567567 pathogenic not provided 2016-10-21 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.380+1G>A or IVS4+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 4 of the MLH1 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also published as MLH1 c.381G>A, has been reported in several individuals/families suspected to have Lynch syndrome (Scott 2001, Mangold 2005a, Mangold 2005b, Schofield 2009). Based on the current evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV001021188 SCV001182769 pathogenic Hereditary cancer-predisposing syndrome 2019-10-14 criteria provided, single submitter clinical testing The c.380+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the MLH1 gene. This variant has been reported in multiple individuals with personal and/or family history consistent with Lynch syndrome (Mangold E et al. Int. J. Cancer. 2005 Sep;116:692-702; Mangold E et al. J. Pathol. 2005 Dec;207:385-95; Schofield L et al. Int. J. Cancer. 2009 Mar;124:1097-102; Ambry internal data). 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353869 SCV000592356 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The c.380+1G>A variant has been identified in 1 out of 3546 proband chromosomes (frequency 0.014) in individuals with hereditary nonpolyposis colorectal cancer (HNPCC): however no normal population controls were included in this study (Mangold 2005). This variant located in the 5’ splice region is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant +1 and +2 positions region of the splice consensus sequence. In summary, based on the above information, this variant is classified as pathogenic.
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249909 SCV001423926 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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