Submissions for variant NM_000249.4(MLH1):c.808A>G (p.Thr270Ala)

gnomAD frequency: 0.00004  dbSNP: rs371302926

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215834	SCV000273633	likely benign	Hereditary cancer-predisposing syndrome	2018-12-12	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.
Counsyl	RCV000412189	SCV000489683	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV000475873	SCV000543644	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985258	SCV000601412	uncertain significance	not provided	2019-02-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000215834	SCV000910976	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505929	SCV000919650	uncertain significance	not specified	2023-03-20	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.808A>G (p.Thr270Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal and DNA mismatch repair protein, S5 domain 2-like domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251456 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.808A>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Seven 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: likely benign (n=4), VUS (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000985258	SCV001803045	likely benign	not provided	2020-08-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV000505929	SCV002064743	uncertain significance	not specified	2020-08-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.808A>G, in exon 10 that results in an amino acid change, p.Thr270Ala. This sequence change does not appear to have been previously described in patients with MLH1-related disorders and has been described in the gnomAD database with a low population frequency of 0.0036% (dbSNP rs371302926). The p.Thr270Ala change affects a moderately conserved amino acid residue located in a domain of the MLH1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr270Ala substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr270Ala change remains unknown at this time.
Myriad Genetics, Inc.	RCV000412189	SCV004020255	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-10	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].
GenomeConnect - Invitae Patient Insights Network	RCV001535606	SCV001749621	not provided	Mismatch repair cancer syndrome 1; Colorectal cancer, hereditary nonpolyposis, type 2		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 06-14-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.