Submissions for variant NM_000249.4(MLH1):c.977T>C (p.Val326Ala)

gnomAD frequency: 0.00037  dbSNP: rs63751049

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075951	SCV000106969	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035356	SCV000059004	likely benign	not specified	2017-07-27	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000590380	SCV000149399	likely benign	not provided	2021-04-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 8574961, 22949387, 9697702, 20176959, 18561205, 10573010, 16736289, 8592341, 16885385, 10446963, 9506527, 10448273, 17594722, 24728327, 23588873, 25637381, 22736432, 24055113, 25871441, 10732761, 21239990, 12810663, 17510385, 21404117, 11781295, 11555625, 17192056, 22290698, 15340264, 10601588, 26976419, 24362816, 20533529, 30998989)
Invitae	RCV001084822	SCV000153900	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115490	SCV000187366	likely benign	Hereditary cancer-predisposing syndrome	2018-09-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590380	SCV000604229	likely benign	not provided	2023-11-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115490	SCV000684887	likely benign	Hereditary cancer-predisposing syndrome	2015-04-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035356	SCV000696195	benign	not specified	2020-11-05	criteria provided, single submitter	clinical testing	Variant summary: The variant, MLH1 c.977T>C (p.Val326Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain 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 0.00048 in 278288 control chromosomes, predominantly at a frequency of 0.0011 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. This variant was found in two affected members from a Lynch family (example, Hardt 2011). Detailed genotypic and phenotypic information was not available to assert whether or not the variant co-segregated with disease. In contrast, in one family, this variant did not co-segregate with the disease: while one affected member was positive for the variant, other two affected members did not carry the variant (Pastrello 2011). In addition, tumor tissues from patients with this variant showed no loss of heterozygosity, normal expression of MLH1 or MSH2, and normal microsatellite instability (Dieumegard 2000, Spaepen 2006, Pastrello 2011, Hardt 2011). In vitro MMR and dominant mutator effect studies showed conflicting results (Shimodaira 1998, Trojan 2002, Takahashi 2007) although supporting a functional MMR activity (Trojan_2002). Furthermore, a yeast two-hybrid assay showed that hMLH1 V326A can interact with hPMS2 and hEXO1 (Kondo 2003) and the variant was shown to not affect normal splicing (Borras 2012). Twelve clinical diagnostic laboratories and one expert panel (INSIGHT) have submitted clinical-significance assessments for this variant to ClinVar without evidence for independent evaluation. Eleven of them, to include the expert panel have classified the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000590380	SCV000805985	likely benign	not provided	2017-02-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000035356	SCV000888191	benign	not specified	2021-08-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000987161	SCV001136392	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590380	SCV001153840	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MLH1: BS1
Sema4, Sema4	RCV000115490	SCV002528792	benign	Hereditary cancer-predisposing syndrome	2020-10-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000035356	SCV002552449	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115490	SCV002819253	benign	Hereditary cancer-predisposing syndrome	2022-12-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149616	SCV003838865	likely benign	Breast and/or ovarian cancer	2023-03-03	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000987161	SCV004015869	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing
ITMI	RCV000035356	SCV000085539	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144598	SCV000189925	likely benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148617	SCV000190332	uncertain significance	Colorectal cancer, non-polyposis	2014-06-01	no assertion criteria provided	research
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000075951	SCV000296892	uncertain significance	Lynch syndrome	2015-12-21	flagged submission	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000035356	SCV000691852	likely benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000115490	SCV000886687	likely benign	Hereditary cancer-predisposing syndrome	2018-09-27	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000590380	SCV001806859	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000035356	SCV001957483	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000035356	SCV002033830	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000035356	SCV002036431	benign	not specified		no assertion criteria provided	clinical testing