Submissions for variant NM_000249.4(MLH1):c.588+5G>A

dbSNP: rs267607768

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075774	SCV000106783	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberrations: full inactivation of variant allele
Invitae	RCV000627715	SCV000253792	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-12	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Lynch syndrome (PMID: 15713769, 16341550, 18561205, 24090359, 26437257; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS07+5G>A. ClinVar contains an entry for this variant (Variation ID: 90285). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7 and introduces a premature termination codon (PMID: 15713769, 16341550, 18561205). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000213543	SCV000279074	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	Intronic +5 splice variant in a gene for which loss-of-function is a known mechanism of disease, and skipping of exon 7 has been observed (Pagenstecher et al., 2006; Peterson et al., 2013; Pinero et al., 2020); Observed in multiple individuals with suspected Lynch syndrome, including those with Lynch related tumors found to be MSI-H and/or show loss of MLH1 via immunohistochemistry (Casey et al., 2005; Wolf et al., 2005; Pagenstecher et al., 2006; Batte et al., 2014; Sunga et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 16341550, 15713769, 15926618, 24933100, 28449805, 18561205, 24090359, 29887214, 30787465, 32363481)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000075774	SCV000592364	pathogenic	Lynch syndrome	2014-03-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213543	SCV000601403	pathogenic	not provided	2021-10-20	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in HNPCC families (PMIDs: 18389388 (2008), 16206289 (2006), 15926618 (2005)). The variant has demonstrated to affect normal MLH1 mRNA splicing, causing a skip of exon 7 (PMIDs: 24090359 (2013), 18561205 (2008), 16341550 (2006)). Based on the available information, this variant is classified as pathogenic.
Ambry Genetics	RCV000572458	SCV000676018	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-06	criteria provided, single submitter	clinical testing	The c.588+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 7 in the MLH1 gene. This intronic mutation has been detected in multiple families meeting Amsterdam and/or Bethesda criteria for HNPCC/Lynch syndrome, with tumor results revealing absence of MLH1 protein expression on immunohistochemistry (Ambry internal data, Casey et al. JAMA. 2005. 293(7): 799–809; Wolf et al. Int J Cancer. 2006. 118(6):1465-70; Pagenstecher et al. Hum Genet. 2006. 119: 9–22; Sunga AY et al. Cancer Genet 2017 04;212-213:1-7). Functional studies have demonstrated aberrant splicing, leading to skipping of exon 7 and a truncated protein product (Pagenstecher et al. Hum Genet. 2006. 119: 9–22; Petersen SM et al. BMC Medical Genetics 2013,14:103; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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.
Fulgent Genetics, Fulgent Genetics	RCV000763100	SCV000893642	pathogenic	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2021-12-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000572458	SCV001349011	pathogenic	Hereditary cancer-predisposing syndrome	2019-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255542	SCV001432009	pathogenic	Hereditary nonpolyposis colon cancer	2020-08-21	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.588+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' splicing donor site and two predict it abolishes it. Experimental evidence from multiple studies supports these predictions demonstrating the variant affects mRNA splicing leading to exon skipping (Casey_2005, Pagenstecher_2006, Tournier_2008, Petersen_2013). The variant was absent in 251328 control chromosomes (gnomAD). c.588+5G>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Casey_2005, Pagenstecher_2006, Wolf_2006, Tournier_2008, Petersen_2013). These data indicate that the variant is likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003452753	SCV004186535	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-17	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18561205].