Submissions for variant NM_000249.4(MLH1):c.2103G>C (p.Gln701His)

dbSNP: rs63750603

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075534	SCV000106531	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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001549279	SCV000696146	pathogenic	Hereditary nonpolyposis colon cancer	2021-07-07	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.2103G>C (p.Gln701His) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. This nucleotide is located at the exon/intron junction at the end of exon 18. Several computational tools predict a significant impact on normal splicing: Four predict that the variant abolishes a 5-prime splicing donor site. This finding has been corroborated by at least one publication reporting experimental evidence that this variant affects mRNA splicing, resulting in the skipping of exon 18 (e.g. Pagenstecher_2006). The variant was absent in 250694 control chromosomes. c.2103G>C has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Hardt_2011, Yanus_2020). These data indicate that the variant is very likely to be associated with disease. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000694604	SCV000823055	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 701 of the MLH1 protein (p.Gln701His). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 15849733, 16341550, 21404117, 30521064, 31491536; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90049). 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 tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 18, but is expected to preserve the integrity of the reading-frame (PMID: 15849733, 16341550). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001014446	SCV001175153	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-14	criteria provided, single submitter	clinical testing	The c.2103G>C pathogenic mutation (also known as p.Q701H) located in coding exon 18 of the MLH1 gene. This pathogenic mutation results from a G to C substitution at nucleotide position 2103. The glutamine at codon 701 is replaced by histidine, an amino acid with highly similar properties. This change occurs in the last base pair of exon 18 which makes it likely to have some effect on normal mRNA splicing. In two studies, RNA analyses showed that this mutation lead to the complete loss of coding exon 18 (Mangold E et al. Int J Cancer. 2005 Sep 20;116(5):692-702; Pagenstecher C. Hum Genet. 2006 Mar;119(1-2):9-22). This mutation has been reported in numerous Lynch syndrome families that met either Amsterdam or Bethesda criteria, and whose tumor analyses showed high microsatellite instability and absent MLH1 expression on IHC (Mangold E et al. Int J Cancer. 2005 Sep 20;116(5):692-702; Pagenstecher C. Hum Genet. 2006 Mar;119(1-2):9-22; Lucci-Cordisco E et al. Cancer Biomark. 2006;2(1-2):11-27; Hardt K et al. Fam Cancer. 2011 Jun;10(2):273-84). In addition, this alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
MGZ Medical Genetics Center	RCV002288570	SCV002579769	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-01-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477468	SCV004220872	pathogenic	not provided	2023-05-16	criteria provided, single submitter	clinical testing	The MLH1 c.2103G>C (p.Gln701His) variant (also known as Q701H) has been reported in the published literature in individuals and families affected with colorectal cancer (PMIDs: 16216036 (2005), 16341550 (2006), 21404117 (2011), 30521064 (2019), 31491536 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Studies of RNA splicing and immunohistochemistry in tumors have shown that this variant causes complete exon skipping and loss of MLH1 expression (PMIDs: 15849733 (2005), 16216036 (2005), 16341550 (2006), 36593122 (2023)). Based on the available information, this variant is classified as pathogenic.
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093697	SCV001250881	pathogenic	Lynch syndrome 1		no assertion criteria provided	clinical testing