Submissions for variant NM_000249.4(MLH1):c.65G>C (p.Gly22Ala)

gnomAD frequency: 0.00016  dbSNP: rs41295280

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075796	SCV000106808	benign	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability <0.001
GeneDx	RCV000656857	SCV000149393	likely benign	not provided	2020-11-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28466842, 25986311, 27930734, 26333163, 17453009, 19224586, 19389263, 22843852, 27150160, 18383312, 16203774, 23729658, 15520370, 22875147, 17117178, 18033691, 25559809, 25871441, 22949387, 30680046)
Ambry Genetics	RCV000115484	SCV000172837	likely benign	Hereditary cancer-predisposing syndrome	2018-05-18	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.
Invitae	RCV001083728	SCV000253141	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000412464	SCV000488206	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-01-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212512	SCV000539647	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 1 LB, 3 VUS (includes expert panel), no new evidence since expert classification
Mendelics	RCV003323287	SCV000837991	benign	Hereditary nonpolyposis colon cancer	2023-08-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765727	SCV000897095	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
Color Diagnostics, LLC DBA Color Health	RCV000115484	SCV000902663	likely benign	Hereditary cancer-predisposing syndrome	2015-12-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656857	SCV001153831	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212512	SCV002014958	benign	not specified	2021-10-18	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.65G>C (p.Gly22Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) 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 0.00013 in 254472 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.00013 vs 0.00071), allowing no conclusion about variant significance. c.65G>C has been reported in the literature in individuals affected with colorectal cancer as well as unaffected controls (example, Fearnhead_2004, Woods_2005, Kets_2006, Barneston_2008, Rouleau_2009, Li_2020). A recent large scale study estimating the likelihood ratios used to compute a tumor characteristic likelihood ratio (TCLR) in combination with in-silico predictors and a multifactorial variant prediction model classified this variant as benign (Li_2020). Multiple co-occurrences with other pathogenic variant(s) have been reported in the UMD database and in the literature (examples, MSH2 c.571_573delCTC, p.Leu191del; MSH2 c.1585delG, p.Glu529LysfsX14; MSH6 c.814G>T, p.Glu272X), providing supporting evidence for a benign role. Multiple clinical diagnostic laboratories and an expert panel (InSiGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments but an emerging consensus towards a benign/likely benign outcome (B/LB, n=5; VUS, n=6). The expert panel has assessed this as a benign variant citing a multifactorial likelihood analysis posterior probability of <0.001. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000115484	SCV002528767	likely benign	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149741	SCV003838346	uncertain significance	Breast and/or ovarian cancer	2022-05-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412464	SCV004020080	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-11-14	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]. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212512	SCV004024885	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656857	SCV004220897	likely benign	not provided	2022-11-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952494	SCV004768966	likely benign	MLH1-related condition	2023-02-01	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
True Health Diagnostics	RCV000115484	SCV000886685	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-13	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358637	SCV001554430	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	MLH1, EXON1, c.65G>C, p.Gly22Ala, Heterozygous, Likely Benign The MLH1 p.Gly22Ala variant was identified in 4 of 2434 proband chromosomes (frequency: 0.002) from individuals with Lynch syndrome, colorectal cancer, or synchronous or metachronous adenomatous polyps, and was present in 3 of 3068 control chromosomes (frequency: 0.001) from healthy individuals (Fearnhead 2004, Woods 2005, Overbeek 2007, Barnetson 2008). The variant was identified in dbSNP (rs41295280) as “with uncertain significance allele”, ClinVar (classified as benign by an InSiGHT expert panel and Invitae; as likely benign by Ambry Genetics and Color; and as uncertain significance by GeneDx and 5 other submitters), UMD-LSDB (observed 5x as neutral and co-occurring with pathogenic mutations: MLH1, c.571-573delCTC, p.Leu191del and MLH1, c.1585delG, p.Glu529LysfsX14). The variant was identified in control databases in 35 of 277,150 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24,034 chromosomes (freq: 0.0002), Other in 2 of 6466 chromosomes (freq: 0.0003), Latino in 1 of 34,420 chromosomes (freq: 0.00003), European in 28 of 126,644 chromosomes (freq: 0.0002), but it was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant was also identified in a patient with a pathogenic variant in MSH6 (c.814G>T, p.Glu272X) and an MSH6-deficient endometrial tumour (Overbeek 2007). The p.Gly22 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000656857	SCV001808946	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000656857	SCV001923761	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656857	SCV001954959	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000656857	SCV001966386	uncertain significance	not provided		no assertion criteria provided	clinical testing