Submissions for variant NM_000249.4(MLH1):c.304G>A (p.Glu102Lys)

dbSNP: rs63750453

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075627	SCV000106629	likely pathogenic	Lynch syndrome 1	2018-06-13	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability > 0.99 (0.995)
Ambry Genetics	RCV000216042	SCV000276633	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-12-04	criteria provided, single submitter	clinical testing	The p.E102K variant (also known as c.304G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide position 304. The glutamic acid at codon 102 is replaced by lysine, an amino acid with similar properties. This variant has been reported in an HNPCC family which met Amsterdam criteria and in vitro studies have found that the c.304G>A nucleotide substitution results in a 5-bp deletion in the 3' end of exon 3 (Nakagawa H et al. Cancer Res. 2002 Aug 15;62(16):4579-82). Additionally, further functional studies have shown decreased or complete loss of MMR function (Ellison AR. et al. Hum. Mol. Genet. 2001:1889-900; Hinrichsen I et al. Clin. Cancer Res. 2013 May; 19(9):2432-41). However, Takahashi et al. also studied the MMR activity of this variant in vitro and found this variant to result in an MMR function of 44.4% compared to 79.7% in WT which they report as inconclusive (Takahashi M et al. Cancer Research. 2007: 4595-60). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000493419	SCV000581719	likely pathogenic	not provided	2024-02-20	criteria provided, single submitter	clinical testing	Functional studies support a damaging effect: most show reduced mismatch repair activity and decreased expression levels (PMID: 11555625, 17510385, 23403630); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 12183410, 18383312, 21642682); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22736432, 18383312, 16395668, 23403630, 11555625, 21642682, 25525159, 16995940, 17510385, 26096739, 23554159, 23741719, 11781295, 14526391, 31857677, 33303966, 22753075, 16083711, 21120944, 11948175, 16341550, 18373977, 34326862, 12183410)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781538	SCV000919653	likely pathogenic	Hereditary nonpolyposis colon cancer	2021-02-15	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.304G>A (p.Glu102Lys) results in a conservative amino acid change located in the N-terminal DNA mismatch repair protein family domain (IPR002099) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. The presence of a cryptic 5' donor site 5 bp upstream of the canonical splice site was however noted at exon 3. Nakagawa et al (2002) suggest that this cryptic splice site is preferentially/exclusively used when the variant is present, resulting in a deletion of the last 5 bp of exon 3, eventually causing a downstream frameshift. A different study however, was unable to detect such an effect and reported no aberrant splicing in relation to the variant (Auclair_2006). Additional functional studies show defective or partially defective MMR activity (Ellison_2001; Hinrichsen_2013; Takahashi_2007, Reyes_2020). The variant was absent in 251344 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with Lynch Syndrome (e.g. Duraturo_2015, Nakagawa_2002). Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely pathogenic (n=5, including one expert panel- International Society for Gastrointestinal Hereditary Tumours (InSiGHT)). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000807476	SCV000947529	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-10	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 11555625, 17510385, 18373977, 23403630). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 18383312). ClinVar contains an entry for this variant (Variation ID: 90141). This missense change has been observed in individuals with Lynch syndrome (PMID: 12183410, 21642682, 22736432, 23729658, 28514183, 31857677). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 102 of the MLH1 protein (p.Glu102Lys).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000493419	SCV001134310	likely pathogenic	not provided	2019-02-15	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/251334 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Results on protein functions were inconclusive.
Color Diagnostics, LLC DBA Color Health	RCV000216042	SCV001340144	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-08-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003451127	SCV004186386	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 12183410, 16341550].
Baylor Genetics	RCV003451127	SCV004195098	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-09-26	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353830	SCV000592348	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	Note: This variant was identified by this lab in a Teresa Minella. IHC not interpretable and MSI results were high.
Mayo Clinic Laboratories, Mayo Clinic	RCV000501856	SCV000691845	uncertain significance	not specified		no assertion criteria provided	clinical testing