Submissions for variant NM_000249.4(MLH1):c.306G>C (p.Glu102Asp)

dbSNP: rs63751665

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075636	SCV000106638	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causing splicing aberration predicted to interrupt known functional domains: full inactivation of variant allele
Invitae	RCV001048439	SCV001212445	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change affects codon 102 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 22736432). ClinVar contains an entry for this variant (Variation ID: 90150). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 3, but is expected to preserve the integrity of the reading-frame (PMID: 22736432). This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Thr82Ala) have been determined to be pathogenic (PMID: 10422993, 17510385, 19690142, 20587412, 21239990, 21404117, 22736432, 23403630, 26300997, 28514183). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002444532	SCV002753909	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-07	criteria provided, single submitter	clinical testing	The c.306G>C pathogenic mutation (also known as p.E102D), located in coding exon 3 of the MLH1 gene, results from a G to C substitution at nucleotide position 306. The amino acid change results in glutamic acid to aspartic acid at codon 102, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. In one study, this alteration, which was also detected with a MLH1 variant with no predicted effect on splicing (c.248G>T), demonstrated in-frame exon 3 skipping upon RT-PCR analysis using patient RNA and no full-length transcript was expressed by the variant allele (Borràs E et al. Hum. Mutat., 2012 Nov;33:1576-88). Another alteration at the same nucleotide position, c.306G>A, which also results in exon 3 skipping, has been classified as pathogenic based on identification in individuals with constitutional mismatch repair deficiency syndrome and Lynch syndrome (Ambry internal data; external communication with outside laboratory). In a functional study, MLH1 p.E102D demonstrated reduced mismatch repair activity (56%) compared to wild type MLH1 (79.7%) in a complementation assay using a human colon cancer cell line, but relative MLH1 protein expression was >75% in the same cell line upon transient expression (Takahashi et al. Cancer Res. 2007. 67(10): 4595-4604). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003451130	SCV004187124	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-12	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 22736432, Myriad internal data].