Submissions for variant NM_000249.4(MLH1):c.91_92delinsTG (p.Ala31Cys)

dbSNP: rs63749994

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590103	SCV000149396	likely benign	not provided	2020-07-20	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27150160, 20020535, 16395668, 21404117, 12624141, 28874130, 27443514, 31159747)
Ambry Genetics	RCV000115487	SCV000185832	likely benign	Hereditary cancer-predisposing syndrome	2018-12-28	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	RCV001081515	SCV000218977	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000410005	SCV000487872	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2015-11-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590103	SCV000601415	likely benign	not provided	2023-07-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115487	SCV000684881	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with cysteine at codon 31 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study reported the variant protein as partially to fully impaired compared to wild-type in an in vitro DNA mismatch repair assay (PMID: 20020535). This variant has been reported in individuals with personal and/or family history of Lynch Syndrome-associated cancers (PMID: 21404117, 27443514, 28874130) and an individual affected with breast or ovarian cancer (PMID: 28828701). This variant is present in gnomAD as combination of two constituent single nucleotide variants in 21 chromosomes, and in all individuals, they are predicted to be located on the same chromosome (in cis). The variant has been identified in 9/30614 chromosomes (0.029%) of South Asians. 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	RCV000235172	SCV000696189	likely benign	not specified	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.91_92delinsTG (p.Ala31Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal and Histidine kinase/HSP90-like ATPase of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.8e-05 in 282508 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (7.8e-05 vs 0.00071), allowing no conclusion about variant significance. c.91_92delinsTG has been reported in the literature in settings of multigene panel testing among individuals affected with a variety of cancers such as (example, Auclair_2006, Hardt_2011, Parc_2003, Ring_2016, Rossi_2017, Zidan_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been observed in the UMD database and at our laboratory (UMD-MSH2 c.1156C>T , p.Arg389X; MLH1 c.1852_1854del; , p.Lys618del ; Our laboratory-BRCA1 c.3700_3704delCTAAA; CHEK2 c.1169A>C, p.Y390S), providing supporting evidence for a benign role. Functional studies show the variant to not affect splicing and to have significantly higher repair activity compared to putatively pathogenic variants, performing slightly comparable to wild type function (Auclair_2006, Drost_2010). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=5; Likely benign/Benign, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA	RCV000115487	SCV000822025	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765729	SCV000897097	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
Revvity Omics, Revvity	RCV000590103	SCV003808829	uncertain significance	not provided	2021-08-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149743	SCV003838857	uncertain significance	Breast and/or ovarian cancer	2021-08-11	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410005	SCV004018154	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	criteria provided, single submitter	clinical testing	This variant is considered likely 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: 25085752].