Submissions for variant NM_000249.4(MLH1):c.2174G>A (p.Arg725His)

gnomAD frequency: 0.00006  dbSNP: rs566928243

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586779	SCV000149382	uncertain significance	not provided	2023-08-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: reduced protein expression, but cellular viability and DNA damage response (DDR) signaling similar to wild type (Arora et al., 2017); Observed in individuals with colorectal cancer or polyps, breast cancer, or endometrial cancer (Chao et al., 2008; Kraus et al., 2015; Shirts et al., 2016; Sung et al., 2017; zdemir et al., 2019); This variant is associated with the following publications: (PMID: 18383312, 25503501, 28125075, 22290698, 25142776, 15184898, 26269718, 26845104, 28961279, 22585170, 31159747, 30238922, 33980423, 32095738, 28494185, 12799449, 20533529, 22753075, 30883245)
Invitae	RCV001079417	SCV000166250	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115473	SCV000184522	likely benign	Hereditary cancer-predisposing syndrome	2018-05-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000075568	SCV000266178	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115473	SCV000537527	likely benign	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212549	SCV000601390	benign	not specified	2020-02-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212549	SCV000696150	uncertain significance	not specified	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.2174G>A (p.Arg725His) 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. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251152 control chromosomes. However, the frequency at which the variant is found in the Ashkenazi Jewish population is higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.0036 vs 0.00071), suggesting the variant may be a polymorphism found in that population. c.2174G>A has been reported in the literature in individuals affected with colorectal, breast, endometrial and pancreatic cancers, without strong evidence for pathogenicity (eg. Chao_2008, Kraus_2015, Lipkin_2004, Shirts_2016, Abe_2019, Ozdemir_2019, Sung_2017, Tsaousis_2019, Solmaz_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, showing reduced expression, but overall reported the variant to be moderately functional (Arora_2017). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five submitters classified the variant as benign (n=2)/likely benign (n=3) while six classified the variant as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneKor MSA	RCV000115473	SCV000822022	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764498	SCV000895569	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001147135	SCV001307917	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory, University of Chicago	RCV000212549	SCV002066725	uncertain significance	not specified	2020-12-31	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.2174G>A, in exon 19 that results in an amino acid change, p.Arg725His. This sequence change has been described in the gnomAD database with a relatively high frequency of 0.35% in the Ashkenazi Jewish sub-population (dbSNP rs566928243). The p.Arg725His change has been described in an individual with breast cancer (PMID: 28961279), an individual with endometrial cancer (PMID: 30238922), and an individual meeting criteria for genetic testing, however specific phenotypic information was not provided (PMID: 31159747). Additionally, a different amino acid change at the same location (p.Arg725Cys) has been reported in association with non-polyposis colorectal cancer (PMID: 18383312). The p.Arg725His change affects a highly conserved amino acid residue located in a domain of the MLH1 protein that is not known to be functional. The p.Arg725His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg725His change remains unknown at this time.
Sema4, Sema4	RCV000115473	SCV002528726	likely benign	Hereditary cancer-predisposing syndrome	2021-06-11	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115473	SCV004014939	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001147135	SCV004018669	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-11-16	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212549	SCV004243156	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000586779	SCV000592444	uncertain significance	not provided		no assertion criteria provided	clinical testing