Submissions for variant NM_000249.4(MLH1):c.1667+1G>A

dbSNP: rs1434898623

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000536108	SCV000625089	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-23	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. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 26248088). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. ClinVar contains an entry for this variant (Variation ID: 455398). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.1667+1G nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 21642682). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000563359	SCV000669523	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-06	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 mutation has been detected in multiple individuals with Lynch syndrome-associated cancers with family histories meeting Amsterdam II criteria (Guindalini RS et al. Gastroenterology, 2015 Nov;149:1446-53; Sunga AY et al. Cancer Genet, 2017 04;212-213:1-7; Ambry internal data). Another alteration impacting the same donor site (c.1667+1G>T) has been detected in a family with Lynch syndrome (Bonadona V et al. JAMA, 2011 Jun;305:2304-10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (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.
Color Diagnostics, LLC DBA Color Health	RCV000563359	SCV001346687	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-10-21	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the +1 position of intron 14 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in 1 individual affected with Lynch syndrome (PMID: 26248088). 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. Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387872	SCV004099586	pathogenic	Hereditary nonpolyposis colon cancer	2023-09-07	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1667+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251200 control chromosomes (gnomAD). c.1667+1G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome (e.g., Guindalini_2015, Sunga_2017, Pearlman_2017, Wang_2019, Kim_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26248088, 27978560, 28449805, 30723297, 35313100). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003449523	SCV004186320	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-21	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15300854].
3DMed Clinical Laboratory Inc	RCV000677882	SCV000804043	pathogenic	Colon cancer	2017-11-02	no assertion criteria provided	clinical testing