Submissions for variant NM_000249.4(MLH1):c.790C>T (p.His264Tyr)

gnomAD frequency: 0.00002  dbSNP: rs63751597

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478542	SCV000565146	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	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; Observed in an individual and parent both with colorectal cancer who both also carried a pathogenic MLH1 variant (Chan et al., 1999); This variant is associated with the following publications: (PMID: 27498913, 23760103, 17192056, 12386821, 18383312, 34426522, 22753075, 21153778, 35031544, 31784484, 23403630, 10956410, 10413423, 30998989)
Invitae	RCV000530665	SCV000625195	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 264 of the MLH1 protein (p.His264Tyr). This variant is present in population databases (rs63751597, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 10413423, 30998989). ClinVar contains an entry for this variant (Variation ID: 90367). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 30998989, 31784484). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 10413423). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000562121	SCV000669560	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-19	criteria provided, single submitter	clinical testing	The p.H264Y variant (also known as c.790C>T), located in coding exon 9 of the MLH1 gene, results from a C to T substitution at nucleotide position 790. The amino acid change results in histidine to tyrosine at codon 264, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). In one functional study, the p.H264Y variant demonstrated restored cytotoxicity to methylation damage in a human colorectal cancer cell line; however, the mean survival score was between those of known damaging and neutral alterations leading to the tentative classification of "potentially neutral" (Bouvet D et al. Gastroenterology. 2019 08;157(2):421-431). This alteration has been reported in a Chinese male diagnosed with a MSI-H colorectal cancer at age 30y which demonstrated absent MLH1 protein expression on IHC. However, authors note that this alteration was detected in conjunction with the MLH1 p.T117M mutation, presumably on the same chromosome (in cis) as this patient's affected mother was also found to carry both alterations (Chan TL et al. J. Natl. Cancer Inst., 1999 Jul;91:1221-6; Lucci-Cordisco E et al. Cancer Biomark, 2006;2:11-27; Yuen ST et al. Oncogene, 2002 Oct;21:7585-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000562121	SCV001345268	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 264 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies report conflicting results for this variant. One study assaying DNA damage tolerance found this variant to be functional (PMID: 30998989), while another study assaying DNA repair activity in mouse cells reported this variant as pathogenic (PMID: 31784484). This variant has been reported in individuals affected with colorectal cancer (PMID: 10413423, 30998989). This variant has been identified in 5/281464 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193965	SCV001363161	uncertain significance	not specified	2019-08-23	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.790C>T (p.His264Tyr) results in a conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Despite the variant being located at the last nucleotide position in exon 9, 5/5 computational tools predict no significant impact on normal splicing. Additionally, no truncated protein product was detected in a patient sample carrying the variant, supporting the lack of impact of this variant on splicing (Chan_1999). The variant allele was found at a frequency of 1.6e-05 in 250062 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.790C>T has been reported in the literature in a mother and son with colorectal cancer who also carried another pathogenic variant MLH1 c.350C>T (p.T117M), providing supporting evidence for a benign role (Chan_1999, Yuen_2002). One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Bouvet_2019). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003483463	SCV004231814	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-09	criteria provided, single submitter	curation	. According to the ACMG standard criteria we chose these criteria: PM2 (supporting pathogenic): popmax:AFR popmax AF:4.82905e-05 popmax AC:2, PP3 (supporting pathogenic): CADD:29.9 REVEL: 0.911 BayesDEL:0.409449
Johns Hopkins Genomics, Johns Hopkins University	RCV003485534	SCV004239098	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-27	criteria provided, single submitter	clinical testing	This MLH1 missense variant has been reported in a mother and son who were both affected with colorectal cancer, and both of them had a second MLH1 variant (c.350C>T; p.Thr117Met) that is known to be pathogenic. c.790C>T (rs63751597) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 5/281464 total alleles; 0.002%; no homozygotes). It has been reported in ClinVar (Variation ID 90367). Two bioinformatic tools queried predict that this substitution would be damaging, and the histidine residue at this position is evolutionarily conserved across most of the species assessed. However, assays studying the effect of this variant on protein function have been inconclusive, with one study suggesting the variant is neutral and another suggesting a pathogenic role. While this variant changes the last nucleotide of exon 9, it is not predicted to affect normal exon 9 splicing, and at least one experimental study supports the lack of an effect on splicing. We consider the clinical significance of c.790C>T in MLH1 to be uncertain at this time.
All of Us Research Program, National Institutes of Health	RCV003997138	SCV004840907	uncertain significance	Lynch syndrome	2023-04-15	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 264 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies report conflicting results for this variant. One study assaying DNA damage tolerance found this variant to be functional (PMID: 30998989), while another study assaying DNA repair activity in mouse cells reported this variant as pathogenic (PMID: 31784484). This variant has been reported in individuals affected colorectal cancer (PMID: 10413423, 30998989). This variant has been identified in 5/281464 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093687	SCV001250870	uncertain significance	Lynch syndrome 1		no assertion criteria provided	clinical testing