Submissions for variant NM_000249.4(MLH1):c.250A>G (p.Lys84Glu)

dbSNP: rs63750641

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075606	SCV000106603	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Abrogated function & >2 MSI-H tumours
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201354	SCV000543580	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-04-29	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 84 of the MLH1 protein (p.Lys84Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 10323887, 17453009, 19419416, 21404117, 26053027). ClinVar contains an entry for this variant (Variation ID: 90120). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt MLH1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 12513688, 15475387, 16083711, 17510385, 21404117, 23403630, 31784484). 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269582	SCV001449670	likely pathogenic	not provided	2017-02-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433575	SCV002745125	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-05-05	criteria provided, single submitter	clinical testing	The p.K84E variant (also known as c.250A>G), located in coding exon 3 of the MLH1 gene, results from an A to G substitution at nucleotide position 250. The lysine at codon 84 is replaced by glutamic acid, an amino acid with similar properties. This alteration was detected in 1 of 93 unrelated families from Taiwan who met Amsterdam Criteria II for a clinical diagnosis of Lynch syndrome (Tang R et al. Clin Genet. 2009 Apr;75(4):334-45). This variant was also detected in an individual whose tumor exhibited high microsatellite instability (Lamberti et al. Gut. 1999 Jun; 44(6): 839-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001269582	SCV004024339	likely pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003451121	SCV004187290	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-12	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16083711].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353981	SCV000592342	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Lys84Glu variant has been reported in the literature in 5 out of 2140 proband chromosomes (frequency of 0.002) from patients with HNPCC; the variant was not reported in any of at least 600 control chromosomes, increasing the likelihood this variant may be a low frequency variant with clinical significance (Ellison 2004, Raevaara 2005, Takahashi 2007, Wanat 2007, Lamberti 1999, Ou 2007, Quaresima 2003, Martinez 2010, Tang 2009, Overbeek 2007). The p.Lys84 residue is conserved across mammals and lower species and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the p.Lys84Glu variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs63750641) but no frequency information was provided so this was not informative for assessing the population frequency. Functional assays using site-directed mutagenesis and in vitro mismatch repair (MMR) assays found the p.Lys84Glu variant to be deficient in MMR function, increasing the likelihood that an alteration to this residue might have clinical significance (Ellison 2004, Raevaara 2005, Takahashi 2007, Wanat 2007, Quaresima 2003). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more pathogenic role for this variant. This variant is classified as Predicted Pathogenic.