Submissions for variant NM_000249.4(MLH1):c.306+5G>A

dbSNP: rs267607735

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075634	SCV000106636	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration leading to truncated protein, >2 MSI-H tumours, co-segregation with disease & MAF 0.0
Fulgent Genetics, Fulgent Genetics	RCV000763099	SCV000893641	pathogenic	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001018363	SCV001179592	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	The c.306+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 3 in the MLH1 gene. This mutation has been identified in numerous families fulfilling Amsterdam I/II criteria and in individuals with tumors demonstrating high microsatellite instability (MSI-H) and/or loss of MLH1/PMS2 protein expression on immunohistochemistry (IHC) (Borras et al. Cancer Res 2010 Oct 1; 70(19):7379-91; Perez-Cabornero et al. Eur J Cancer 2009 May; 45(8): 1485-93, Pérez-Cabornero et al. J Mol Diagn 2013 May;15(3):380-90; Rossi BM et al. BMC Cancer, 2017 Sep;17:623, Ambry internal data). RNA analyses by these authors have demonstrated that this mutation generates an aberrant mRNA transcript resulting in premature protein truncation. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Haplotype analysis supports c.306+5G>A as a founder mutation of Spanish origin (Borras et al. Cancer Res 2010 Oct 1; 70(19):7379-91). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001045822	SCV001209696	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-01-16	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. It affects a nucleotide within the consensus splice site. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this variant affects MLH1 function (PMID: 19250818). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 90148). This variant is also known as IVS3+5G>A. This variant has been observed in individuals with Lynch syndrome (PMID: 16142001, 23523604, 28874130). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).
GeneDx	RCV000202186	SCV001825374	pathogenic	not provided	2023-07-03	criteria provided, single submitter	clinical testing	Common founder variant in the Spanish population (Borras et al., 2010); Intronic +5 splice variant in a gene for which loss-of-function is a known mechanism of disease, demonstrated to result in impaired splicing and aberrant transcript (Perez-Cabornero et al., 2009; Borras et al., 2010); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Martinez-Bouzas et al., 2009; Perez-Carbonero et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 21778331, 22864660, 19250818, 25525159, 16142001, 28874130, 19760518, 24344984, 23554159, 25345868, 21972078, 23523604, 20858721)
Color Diagnostics, LLC DBA Color Health	RCV001018363	SCV002053463	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-02	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 3 of the MLH1 gene. Functional RNA studies have shown that this variant causes use of a cryptic site in exon 3 resulting in premature truncation. This variant has been reported in multiple individuals affected with Lynch syndrome (PMID: 16142001, 19760518, 20858721, 23523604, 28874130) and is a common pathogenic variant in people of Spanish ancestry. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
OMIM	RCV000022504	SCV000043793	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2010-10-01	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000202186	SCV000257094	pathogenic	not provided		no assertion criteria provided	research
GeneReviews	RCV001804820	SCV002054092	not provided	Lynch syndrome 1		no assertion provided	literature only